Fondazione Intergruppo Italiano Linfomi-ONLUSDec 05, 2008 · E-mail: [email protected] •...

Fondazione Intergruppo Italiano Linfomi-ONLUS

Sede legale : piazza Turati 5, 15100 - Alessandria Segreteria: c/o Ematologia Ospedale Civile di Alessandria, Via Venezia 18, 15100 – Alessandria

Tel 0131-206156-206262; Fax 0131-261029; e-mail: [email protected] ; sito web: www.iilinf.it

PROTOCOL DRAFT

IIL STUDY (IIL-HD0801)

Early salvage with high-dose chemotherapy and stem cell transplantation in advanced stage Hodgkin’s lymphoma

patients with positive positron emission tomography after two courses of ABVD (PET-2 positive) and comparison of

radiotherapy versus no radiotherapy in PET-2 negative patients.

Versione 1 Data: 12/5/2008

Versione 1 del 12/05/2008


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STUDY COORDINATORS • Pier Luigi Zinzani, MD

Address: Istituto di Ematologia “L e A Seragnoli”, Policlinico Sant’Orsola. Via Massarenti 9 Bologna Telephone: +39-051-6363973 Fax: +39-051-6364037 E-mail: [email protected]

• Alessandro Levis, MD Address: Divisione di Ematologia, Ospedale SS Antonio e Biagio. Via Venezia 16. Alessandria Telephone: +39-0131-206262 Fax: +39-0131-261029 E-mail: [email protected]

WRITING COMMITTEE • Ercole Brusamolino (Pavia)

• Angelo Michele Carella (Genova)

• Antonio Castagnoli (Prato)

• Giovannino Ciccone (Torino)

• Alessandro Levis (Alessandria)

• Umberto Ricardi (Torino)

• Luigi Rigacci (Firenze)

• Armando Santoro (Rozzano)

• Pier Luigi Zinzani (Bologna)

BIOMETRY • Giovannino Ciccone, MD

Address: S.C.D.U. Epidemiologia dei Tumori, Università e Azienda Ospedaliera S. Giovanni Battista, Torino. Corso Bramante 88 – 10126 - Torino Telephone: 0039-011-6336857 Fax: 0039-011-6706692 E-mail: [email protected]

FARMACO-VIGILANCE • Alessandro Levis, MD

Address: S.O.C. di Ematologia, Azienda Ospedaliera SS Antonio e Biagio, Alessandria. Via Venezia 18 – 15100 - Alessandria Telephone: 0039-0131-206262 Fax: 0039-0131-261029 E-mail: [email protected]

mailto:[email protected]



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TABLE OF CONTENTS

page Synopsis 4 Background 8 Study definition 11 Study objectives 11 Number of participating centres 12 Inclusion criteria 12 Exclusion criteria 12 End points and response criteria 12 Trial design and treatment 15 Radiotherapy 17 Salvage treatment of early-PET-positive patients 17 PET evaluation 18 Toxicity and adverse events evaluation 18 Clinical evaluation and laboratory tests 20 Statistical considerations 20 Study duration 23 Bibliography 24 Appendix A – Study flow chart 26 Appendix B – Flow chart of salvage of PET-2 positive patients 27 Appendix C – Enrolment and randomization procedures 28 Appendix D – Summary table of required investigations 29 Appendix E – ECOG performance status 32 Appendix F – ABVD chemotherapy 33 Appendix G – IGEV chemotherapy 34 Appendix H – BEAM chemotherapy 35 Appendix I – High dose melphalan chemotherapy 36 Appendix L – Anti-emetic and supportive treatment 37 Appendix M – Radiotherapy guidelines 38 Appendix N – Foglio informativo per il curante 41 Appendix O – Foglio informativo per il paziente 44 Appendix P – Informed consent 49 Appendix Q – Grading of toxicity 52 Appendix R – Criteria and instructions for PET evaluation and reviewing 53 Appendix S – Instruction for PET centralized review 58


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SYNOPSIS

TITLE Early salvage with high dose chemotherapy and stem cell transplantation in advanced stage Hodgkin’s lymphoma patients with positive positron emission tomography after two courses of ABVD (PET-2 positive) and comparison of radiotherapy versus no radiotherapy in PET-2 negative patients.

VERSION November 2nd 2007 SPONSOR This is a non-profit study. There is no commercial sponsor.

The non-profit sponsor is the “Fondazione Intergruppo Italiano Linfomi ONLUS (IIL ONLUS)”. No experimental drugs are utilized. The ABVD chemotherapy is the standard treatment for Hodgkin’s lymphoma and it is based on drugs approved for this indication.

STUDY PHASE - PET-2 positive patients: Phase II multi-centre study. - PET-2 negative patients: Phase III multi-centre randomized study.

COORDINATORS Pier Luigi Zinzani, Alessandro Levis WRITING COMMITTEE Ercole Brusamolino, Angelo Michele Carella, Antonio Castagnoli, Giovannino

Ciccone, Alessandro Levis, Umberto Ricardi, Luigi Rigacci, Armando Santoro, Pier Luigi Zinzani.

DATA MANAGER AND STATISTICIAN

Giovannino Ciccone (CPO Piemonte). Registration, randomization and data collection will be performed on line (web site EPICLIN: www.epiclin.cpo.it).

POPULATION Patients affected with advanced stage (stage IIB-IV) Hodgkin’s lymphoma. STUDY OBJECTIVES • To evaluate if patients resistant to the initial treatment for residual PET-

positive masses after the first two courses of ABVD (PET-2 positive), can be salvaged by early shift to high-dose chemotherapy supported by stem cell rescue (according to the high-dose salvage IIL-HD0802 protocol).

• To analyse if patients achieving early complete response (PET-2 negative), can be spared the adjuvant radiotherapy on areas of initial bulky disease, at the end of the planned six courses of ABVD. To answer this question, PET-2 negative patients will be randomized between radiotherapy versus no radiotherapy at the end of ABVD therapy.

PARTECIPATING CENTRES

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INCLUSION CRITERIA Inclusion criteria Histologically confirmed Hodgkin’s lymphoma of the classical type (nodular

lymphocyte predominance excluded) Stage IIB-IV. Age 18-70. No prior therapy for Hodgkin’s lymphoma Written informed consent. ECOG performance status grades 0-3 (see Appendix E) FDG-PET scan before the initiation of treatment.

Exclusion criteria Prior therapy for Hodgkin’s lymphoma. Age less than 18 or more than 70. Other concomitant or prior malignancies, except basal cell skin carcinoma,

or adequately treated carcinoma in situ of the cervix, or any cancer in complete remission for more than 5 years.

HIV infection. Pregnancy or breast-feeding. Renal failure (creatinine ≥ 2 times the normal value), liver failure (AST/ALT

or bilirubine ≥ 2.5 times the normal value) or heart failure (NYHA class ≥ 2 or FEV < 45%).


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ENDPOINTS For PET-2 positive patientsa) Primary end point

- 2-year progression free survival (PFS) rate (according to Cheson criteria). Events are considered the disease progression and deaths from any cause

b) Secondary end points - Complete remission rate (CR). - 2-year overall survival (OS) rate. - 2-year time to progression (TTP) rate.

For PET-2 negative patients a) Primary end point

- 2-year event free survival (EFS) rate. Events are considered the disease progression, secondary cancers, late serious treatment-related events and deaths from any cause.

b) Secondary end points - 2-year progression free survival (PFS) rate. - 2-year relapse free survival (RFS) rate. - 2-year overall survival (OS) rate. - Cost-effectiveness comparison between the two arms. - Percentage of PET-6 positive patients (cost-effectiveness of

repeating PET at the end of six ABVD in patients already negative after the first two ABVD).

RANDOMIZATION FOR PET-2 NEGATIVE PATIENTS

PET-2 negative patients will be randomized, at the end of the six courses of ABVD chemotherapy, between radiotherapy on areas of initial bulky disease versus no radiotherapy.

PHARMACO-VIGILANCE AND MONITORING ACTIVITIES

The incidence and severity of serious adverse events (SAE) and unexpected serious adverse reactions (SUSAR) will be registered according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0). Alessandro Levis, Secretary of the IIL ONLUS Foundation, will be responsible for the pharmaco-vigilance and the monitoring activities.

TREATMENT The study flow chart is illustrated in the Appendix A. The flow chart of salvage treatment for PET-2 positive patients is illustrated in the Appendix B. 1) Staging

• Histologically confirmed diagnosis of Hodgkin’s lymphoma. • Staging procedures include thorax, abdomen and pelvis CT scan,

whole body FDG-PET and unilateral bone marrow biopsy.

2) First-line treatment • Two courses of ABVD. • Early restaging with FDG-PET scan (PET-2) • The subsequent treatment will be as it follows:

1. PET-2 positive patients will be treated with high-dose salvage treatment as detailed in the salvage IIL protocol HD0802 and summarized in the salvage section of this protocol.

2. PET-2 negative patients will be treated with four additional courses of ABVD (for a total of six courses).

• The following restaging procedures are planned as it follows: Optional: Whole body CT scan after the fourth course of ABVD;

no therapy change will be made according to CT scan. Mandatory: Whole body CT and FDG-PET scans after the sixth

course of ABVD (PET-6). PET-6 negative patients will be randomized to one of the following arms:

No radiotherapy.


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Adjuvant radiotherapy (30 Gy) on sites of initial bulky disease. PET-6 positive patients will be treated with the IIL HD0802 protocol.

ABVD courses are scheduled every 28 days (see Appendix F):

Doxorubicin 25 mg/m2 i.v. day 1 and 15 Bleomycin 10 mg/m2 i.v. day 1 and 15 Vinblastine 6 mg/m2 i.v. day 1 and 15 Dacarbazine 375 mg/m2 i.v. day 1 and 15

3) Salvage treatment for PET-2 positive patients These patients will be treated according to the IIL HD0802 salvage protocol, summarized as it follows: • PET-2 positive patients will receive four courses of the IGEV

chemotherapy. • IGEV courses are scheduled every 21 days (see Appendix G):

Ifosphamide 2000 mg/m2 i.v. days 1 to 4 Gemcitabine 800 mg/m2 i.v. days 1 and 4 Vinorelbine 20 mg/m2 i.v. day 1 Prednisolone 100 mg tot days 1 to 4

• Lenograstim at the dose of 5μg/kg/die will be administered from day 7 to the recovery from severe neutropenia (neutrophils > 500/mm3) or to the completion of peripheral blood stem cell collection.

• Peripheral blood stem cell collection and harvesting will be carried out after the third course of IGEV. The optimal target number of CD34+ cells to be collected is 4x106/Kg, with minimum amount of 2x106/Kg.

• A FDG-PET evaluation (PET-IGEV) will be carried out at the end of the fourth course of IGEV. Subsequent therapy will be planned according to PET-IGEV results as it follows: - PET-IGEV negative patients will receive high-dose BEAM

chemotherapy followed by autologous peripheral blood stem cell infusion (see protocol IIL HD0802)

- PET-IGEV positive patients will receive high dose melphalan chemotherapy followed by autologous peripheral blood stem cell infusion. Patients with HLA-identical donor will then proceed to allogeneic peripheral blood stem cell transplantation after reduced intensity conditioning. Patients with no HLA-identical donor will undergo a second autologous peripheral blood stem cell transplantation after conditioning with the high-dose BEAM regimen.

4) Follow up

The follow up procedures will include clinical and laboratory evaluation every four months. CT and FDG-PET scans will be carried-out yearly for the first five years of follow-up

TREATMENT DISCONTINUATION

The criteria for therapy discontinuation are as it follows: • Completion of planned therapy. • Disease progression during therapy. • Severe toxicity not allowing therapy delivery according to the protocol • Lack of FGD-PET evaluation after the second course of ABDV (major

protocol violation). • Refusal of patient, at any time and for any reason. • Principal investigator’s decision.

SAMPLE SIZE 1. Phase II study (PET-2 positive patients) sample size. The 2-year PFS rate of PET-2 positive patients treated with six courses of ABVD or ABVD-like regimens is about 10-15%. With high-dose chemotherapy, a salvage rate of at least 35% is considered to be clinically relevant. The sample size has been estimated according to the Fleming


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design, assuming: - Alpha error = 0.05 - Beta error = 0.05 - EFS0 (the maximum 2-year PFS achievable with standard treatments) =

0.15 - EFS1 (the minimum 2-year PFS expected with the high dose salvage

therapy) = 0.35 This study requires 52 patients to decide whether the 2-year EFS is less than or equal to 15% or greater than or equal to 35%.

2. Phase III study (PET-2 negative patients) sample size The primary end point for the phase III study, comparing radiotherapy vs no radiotherapy in PET-2 negative patients, is 2-year EFS. The sample size of the study has been estimated assuming: - Alpha error = 0.05 - Beta error = 0.20 - 2-year EFS in the RT arm = 0.60 - 2-year EFS in the No RT arm = 0.80 - Accrual period (constant) = 4 years - Minimum follow up = 2 years A two-sided log rank test with an overall sample size of 120 subjects (of which 60 in the RT arm and 60 are in the No-RT arm) achieves 80% power at a 0.05 significance level to detect a difference of 0.20 between 0.60 and 0.80 - the proportions of event-free patients at 3 years in each group.

3. Overall sample size Taking into account the required sample size of the two studies (N=52 for the phase II study on PET-2 positive patients and N=120 for the phase III study on PET-2 negative patients with initial bulky disease), and considering that: the proportion of PET-2 positive patients is expected to be about 20%

(n=60 patients eligible for the phase II study); out of 240 PET-2 negative patients, about 55% (N=132) are expected to

have initial bulky disease and to be eligible for the phase III study The total number of patients to be enrolled at diagnosis is about 300

STUDY DURATION 72 months: • 48 months for patient enrollment • 24 months for a minimal 12-month follow-up after the last patient enrolled


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BACKGROUND Advanced Hodgkin’s lymphoma (HL) was nearly always a fatal disease until the

development of combination chemotherapy. The first widely used multi-agent MOPP

chemotherapy produced a response rate of 80% and a long-term disease-free survival of

about 50% (1, 2). The ABVD regimen, developed in 1973, showed to be non cross

resistant with the MOPP and to cure about 25% of patients refractory to MOPP or

relapsing after MOPP (3). The hybrid or alternating MOPP and ABVD combinations were

widely tested in the 1980s and have shown to be superior to MOPP (4, 5). In advanced

Hodgkin’s disease, a large randomized CALGB trial has compared MOPP with ABVD and

with MOPP alternating to ABVD. Both the ABVD and the alternating MOPP and ABVD

regimens proved to be superior to MOPP in terms of progression-free survival (4). These

results were confirmed in a large U.S. Intergroup study in which the MOPP/ABV hybrid

regimen was tested against ABVD (6). This trial enrolled 856 patients and no differences

were found between the two programs in terms of complete response, freedom from

treatment failure or overall survival rate.

The conclusion to draw from these trials is that the ABVD regimen presently offers the

best trade-off between good efficacy and low toxicity and should therefore be considered

the standard of care for advanced-stage HL. This conclusion, however, is challenged by a

37% failure rate after ABVD and a 18% death rate in a median follow-up of 5-years (about

half of total deaths are due to progressive disease). Moreover, the 15-year updated

CALGB data (7) have shown that after ABVD the failure-free survival rate is 50% and the

overall survival 65%.

In 1992, the German Hodgkin Study Group (GHSG) designed the BEACOPP

combination that includes some of the drugs utilized in the alternating COPP/ABVD

program with the addition of etoposide and the exclusion of vinblastine and dacarbazine

The BEACOPP regimen, in both its baseline and dose-escalated variants, has

substantially increased dose-density and dose-intensity compared to the ABVD and the

alternating regimens. In the HD9 randomized trial, the GHSG has compared the

alternating COPP/ABVD with baseline BEACOPP and with the escalated BEACOPP

chemotherapy. Radiotherapy was administered only on bulky disease or on residual

disease after chemotherapy. In the final analysis on 1201 patients (8), a significant

superiority was demonstrated for escalated BEACOPP (87%) versus baseline BEACOPP

(76%) and COPP/ABVD (69%). Besides, the escalated BEACOPP overcomes, at least in

part, the significance of the International Prognostic Score (IPS). As expected, the


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escalated BEACOPP was associated with a significantly greater haematological toxicity

and a higher transfusional requirement. Considering the results obtained with the ABVD,

about half of the patients with advanced disease are potentially over-treated with the

escalated BEACOPP program; therefore, new biologic or gene expression profile markers

are being evaluated to identify high-risk categories deserving a more intensive approach

compared to the standard ABVD. The role of the FDG-PET (18-Fluoro-deoxy-D-glucose

Positron Emission Tomography) functional imaging to demonstrate the chemosensitivity of

HL and to predict the outcome has recently been emphasized. The patients who become

FDG-PET negative after two courses of ABVD (PET-2) have shown an excellent outcome,

with a very low probability of relapse; at variance, patients who remain PET-2 positive are

at high risk of progression (9, 10). The prognostic value of PET-2 evaluation is

independent from the IPS variables and can therefore be considered, so far, the best

available prognostic indicator in advanced Hodgkin’s lymphoma (11). Accordingly, a

treatment strategy tailored on the early response to ABVD, evaluated with FDG-PET after

the first two courses (PET-2 oriented), deserves controlled clinical evaluation. In such a

trial, PET-2 negative patients should complete the ABVD program, while PET-2 positive

patients should switch to early intensified salvage chemotherapy. This approach is

intended to spare the high toxicity of front-line BEACOPP, and to early identify poor

prognosis patients who are candidate for an intensive salvage treatment.

So far, the potential best salvage strategy for PET-2 positive patients is difficult to

delineate. A proportion of these patients could benefit from a conventional non-cross

resistant regimen such as the escalated BEACOPP; however, considering their very

unfavourable outcome in retrospective studies (10-11), an even more dose-intensive

treatment including the early autologous stem cell transplantation could be considered.

Moreover it is well demonstrated that, even with high dose chemotherapy, only

chemosensitive patients show a good probability of cure (14,15). In fact a single

autologous procedure is not sufficient in relapsing patients who are poor responders to the

debulking chemotherapy, and a double autologous transplantation (16) or an autologous

transplantation followed by a reduced conditioning allogenic transplantation (17,18) can be

considered. There is debate about the existence of graft versus lymphoma in HL, but the

role of allogenic transplantation is suggested by many authors. In PET-2 positive patients it

seem therefore rational a salvage program that include a non-cross debulking

chemotherapy schedule such as IGEV (19) with peripheral stem cell harvesting followed

by one of the two following treatment options based on IGEV response: a) one high dose

chemotherapy followed by autologous stem cell rescue in patients already in complete


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remission after the IGEV chemotherapy; b) the same autologous procedure followed by

either a reduced-intensity conditioning (RIC) allogenic transplantation or a second

autologous procedure according to the availability of a HLA-identical stem cell donor in

patients who are not in complete remission after the IGEV chemotherapy.

Another burning question in the subset of advanced HL patients is if they really need

radiotherapy after effective chemotherapy. So far almost all advanced stage patients

responding to conventional chemotherapy have been treated with complementary

radiotherapy on the areas of initial bulky disease or residual masses. The rationale for the

use of radiation therapy as an adjuvant to chemotherapy in stage III and IV patients is

based on the observations of relapse in previously involved sites, most often bulky lymph

nodes, even in patients with stage IV disease. Although well tolerated acutely,

radiotherapy is associated with an increased risk of second cancers and ischemic heart

disease, on the basis of dose, volume and other technical factors. The GELA compared, in

advanced-stage HL patients entering CR or PR after 6 courses of ABVPP or MOPP/ABV,

2 further courses of chemotherapy versus sub-total–nodal irradiation, and showed that

radiotherapy was not superior to consolidation chemotherapy (20). The radiotherapy did

not show to be superior to chemotherapy alone even in the small subgroup of patients with

bulky mediastinal mass (21). Similar results were obtained from the EORTC group that

demonstrated that patients entering CR after 6-8 courses of MOPP/ABV do not benefit

from complementary involved field radiotherapy and fared as well as the primary CR

patients. However in this study a sub-group analysis for patients with bulky disease, that

accounted for about one third of the total of randomised patients has not been performed

(22). In the EORTC study, patients in PR after chemotherapy who were considered to

have active residual disease, were all scheduled to receive involved-field radiotherapy. In

this experience, these patients had 8-year event-free survival and overall survival rates

similar to those of patients in CR, suggesting a definite role for RT in this setting; as

expected, significantly more patients with bulky disease at the start of treatment were

found in the PR group, with a significantly decreased probability of CR in the case of bulky

mediastinal disease (45% vs 62%, p=0.001). It is likely that among patients in PR, a

substantial proportion did not truly have active residual disease and were possibly

overtreated with IF-RT, in the absence of modern imaging techniques for response

evaluation during the inclusion period of the EORTC study; but it is also possible to argue

for an indirect proof of efficacy of consolidation RT on initial bulky disease (23).

Furthermore the GHSG H12 study (24) has demonstrated that after 8 CT cycles there

was no difference between the RT+ or RT- arms in an intention to treat analysis. All these


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data suggest that conventional radiotherapy on areas of initial bulky disease is not really

needed in patients obtaining CR with chemotherapy, even if a randomised comparison has

never been performed in patients treated with only 6 courses of ABVD. The evidence in

favour of consolidation radiotherapy in patients with bulky disease achieving CR after 6

courses of ABVD coming from the randomized Indian study (25) is biased from several

methodological issues relative to that study.

It is therefore useful a randomised comparison, within the group of favourable PET-2

negative patients treated with 6 ABVD, of the administration of consolidation radiotherapy

on initial bulky areas against no further treatment. Patients with residual disease of any

size on CT scans will be considered in CR if PET negative.

A recent analysis has shown a poor prognosis of patients with a late CT scan response

improvement (from course 4 to six) (26). In the favourable group of PET-2 patients it is of

interest to analyse, as optional part of this study, if there is some late responding patients

whose prognosis is less favourable of all other PET-2 negative patients.

STUDY DEFINITION A phase II multi-centre study evaluating in patients with advanced stage Hodgkin

lymphoma the efficacy of an early salvage treatment with high-dose chemotherapy

followed by stem cell transplantation in patients FDG-PET positive after two courses of

ABVD (PET-2 positive).

A phase III randomised study comparing the efficacy of radiotherapy to the areas of

initial bulky disease versus no further therapy in PET-2 negative patients in complete

remission (PET-6 negative) at the end of six courses of ABVD.

STUDY OBJECTIVES Primary objective

To evaluate if patients considered a failure of the initial treatment, for residual PET

positivity after the first two courses of ABVD (PET-2 positive), can be salvaged with an

early shift to high-dose chemotherapy supported by stem cell rescue.

Secondary objective

To analyse if patients entering an early complete response (PET-2 negative), can be

spared subsequent radiotherapy on areas of initial bulky disease, at the end of the planned


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six courses of ABVD. In order to answer this question, PET-2 negative patients are

randomized between radiotherapy on initial bulky disease areas versus no radiotherapy.

NUMBER OF PARTECIPATING CENTRES 50 Italian hematological Centres.

INCLUSION CRITERIA Histologically confirmed diagnosis of Hodgkin’s lymphoma, with the exclusion of

nodular lymphocyte predominance.

Age 18-70.

Stage IIB-IV.

No prior therapy.

ECOG performance status grades 0-3 (see Appendix 4)

FDG-PET scan performed before treatment. Written Informed Consent.

EXCLUSION CRITERIA Age less than 18 or more than 70.

Prior therapy for Hodgkin’s lymphoma.

Other concomitant or prior malignancies, with the exception of basal cell skin

carcinoma, of adequately treated carcinoma in situ of the cervix and of any cancer in

complete remission for more than 5 years.

Pregnancy or breast-feeding.

Clinically significant cardiac disease, including congestive heart failure, that can

contraindicate the treatment with anthracyclines (NYHA class ≥ 2 or FEV < 45%).

HIV infection.

Any other contraindication to ABVD, such as renal failure (creatinine level more than

two times the normal value) or hepatic failure (AST/ALT or bilirubine more than 2.5

times the normal value).

• Concomitant participation to a study in which investigational drugs are tested.

• Absence of a written Informed Consent.


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END POINTS AND RESPONSE CRITERIA End points and response criteria are defined according to the International Working

Group (IWG) response criteria for malignant lymphoma revised by Cheson et al (27).

END POINTS for the phase II study on PET-2 positive patients

a) Primary end point:

- 2-year progression free survival (PFS) rate. Events are considered the disease

progression and deaths from any cause.

b) Secondary end points:

- Complete remission rate (CR).

- 2-year overall survival (OS) rate.

- 2-year time to progression (TTP) rate.

END POINTS for phase III study on PET-2 negative patients

a) Primary end point:

- 2-year event free survival (EFS) rate. Events are considered the disease

progression, the late serious treatment-related events, secondary cancers, and

deaths from any cause.

b) Secondary end points:

- 2-year progression free survival (PFS) rate.

- 2-year relapse free survival (RFS) rate.

- 2-year overall survival (OS) rate.

- Cost-effectiveness comparison between the two arms.

- Evaluate the percent of PET-6 positive cases (cost-effectiveness of repeating

PET at the end of six courses of ABVD in patients negative after the first two

courses).

• End points and response criteria definition

Response Evaluation

- Complete Remission (CR). Complete disappearance of all detectable clinical

evidence of disease and disease-related symptoms, if present before therapy.

Residual mass of any size is permitted if FDG-PET negative. If bone marrow

was involved by lymphoma before treatment, the infiltrate must have cleared on

repeated bone marrow biopsy. CR evaluation is based on FDG-PET and the old

category of CRu is no longer contemplated. At the end of treatment, patients

must be classified as being either in complete or in partial remission.

- Partial Remission (PR). The designation of PR requires all of the following:


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At least 50% decrease in sum of the product of the diameters (SPD) of up to 6

largest dominant masses. They should be measurable in at least 2

perpendicular dimensions; if possible they should be from disparate regions of

the body; they should include mediastinal and retroperitoneal areas of disease,

whenever these sites are involved.

o No increase should be observed in the size of other nodes, liver, or spleen.

o Splenic and hepatic nodules must regress by ≥ 50% in their SPD, or, for

single nodules in the greatest transverse diameter.

o With the exception of splenic and liver nodules, involvement of other organs

is usually assessable and no measurable disease should be present.

o Patients who achieve CR, but who have persistent morphologic bone marrow

involvement will be considered partial responders. When a bone marrow was

involved before therapy a second biopsy should always be performed at the

end of treatment. If the second biopsy at the end of treatment was not

performed patients should be considered partial responders.

o No new sites of disease should be observed

o The FDG-PET scan should be positive in at least one prior involved site.

- Stable disease (SD)

A patient is considered to have a SD when he or she fails to attain the criteria

needed for a CR or PR, but does not fulfil those for progressive disease.

FDG-PET should be positive at prior sites of disease, with no new areas of

involvement.

- Relapsed disease or Progressive disease (PD)

Progressive disease is defined as the appearance of any new lesion more than

1,5 cm. in any axis, even if other lesions are decreasing in size. Increased FDG

uptake in a previous unaffected site should only be considered relapsed or

progressive disease after confirmation with other modalities. At least 50%

increase from nadir in the SPD of any previously involved nodes, or in a single

involved node, or the size of other lesions (splenic or hepatic nodes). At least

50% increase in the longest diameter of any single previously identified node

more than 1 cm. in its short axis. Lesions should be FDG-PET positive.

Measurable extranodal disease should be assessed in a manner similar to that

adopted for nodal disease.

- Overall Survival (OS)


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OS is calculated for all patients and it is defined as the time from entry into the

clinical trial (registration) until death from any cause or the date of the last follow-

up

- Progression Free Survival (PFS)

PFS is calculated for all patients and is defined as the time from entry into the

study (registration) until lymphoma progression or death from any cause. In the

phase III study for PET-2 negative patients, those with minor or no response

without progression at the end of planned therapy are considered failures and

switched to second-line therapy. Because in the calculation of PFS time, all

failures are censored when starting second line of therapy, PFS is not the

optimal primary end-point for PET-2 negative patients where the goal is not

disease control (no progression), but cure (no relapses and/or late toxicities).

PFS is therefore considered in this study a secondary end-point.

- Event Free Survival (EFS)

EFS (time to treatment failure) is calculated for all patients and is defined as the

time from entry into the study to treatment failure including disease progression,

or discontinuation of treatment for any reason (disease progression, toxicity,

patient preference, initiation of new treatment without documented progression,

or death). Even if not generally encouraged as primary end-point, this is the best

indicator of cure rate because it combines treatment efficacy, toxicity and patient

compliance to therapy. This is a good end-point in PET-2 negative patients

where the end point is cure without acute or late toxicity.

Relapse free survival or response duration (RFS)

RFS is calculated for patients entering CR and is measured from the time of

attainment of CR to the disease relapse. This is the indicator of duration of

complete response.

TRIAL DESIGN AND TREATMENT The trial design is summarised in the Appendix A. The flow-chart of the salvage therapy for

PET-2 positive patients is shown in the Appendix B. The enrolment and randomisation

procedures are summarized in the Appendix C.

Staging Eligible patients, after their informed consent for the trial, will be staged with both CT and

FDG-PET scans. Baseline staging procedures are summarised in the Appendix D1. The

stage of the disease will be defined according to the Cotswolds meeting criteria (28). The


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nodal bulk will be defined by the largest dimension (in cm) of a single node or of a

conglomerate nodal mass using the CT scan. According to the Stanford criteria (29), a

node or a nodal mass greater than 5 cm will be defined as bulky. A mediastinal mass will

be defined as bulky, when its maximum width on a postero-anterior chest X-ray is equal or

greater then 1/3 of the internal transverse diameter of the thorax at the level of T5/T6 (the

chest X-ray should be taken with maximal inspiration in the upright position with a source-

skin distance of 2 meters.

Phase 1: Initial treatment

All patients will be given two courses of ABVD regimen according to the conventional

schedule summarized in the Appendix F. The anti-emetic and supportive measures are

summarised in the Appendix L.

An FDG-PET (PET-2) scan will be planned 53 to 55 days after the initiation of treatment

and will be done at least 10 days after the second part of the second course of ABVD. The

PET-2 scans will then be sent to the Central Panel for revision according to the Instruction

summarized in the Appendix R.

Phase 2: Treatment prosecution according to PET-2 evaluation According to PET-2 results, the patients will be allocated to one of the two following

treatments:

a) PET-2 negative patients

All PET-2 negative patients will be given four additional courses of ABVD for a total of

six courses.

An optional CT scan may considered, after four courses of ABVD, with no therapy

modification based on its result. Patients will be restaged with both CT and FDG-PET

scan (PET-6) at the end of the whole program of six ABVD.

- Patients in complete remission (PET-6 negative) will be randomised to one of

the two following arms:

A) no radiotherapy and stop of therapy

B) radiotherapy limited to areas of initial bulky disease.

- PET-6 positive patients and/or patients showing disease progression will be

considered refractory and treated with the same salvage program adopted for

early PET-2 positive patients (IIL HD0802 protocol).

b) PET-2 positive patients

All PET-2 positive patients will be treated according to the salvage IIL HD0802

protocol.

c) PET-2 indeterminate patients


17

They will undergo the PET Central Panel review and defined as positive or negative

according to its final decision. While expecting the panel decision, they will be given the

first part of the third course of ABVD.

RADIOTHERAPY Radiotherapy will be delivered in patients in CR (patients with residual disease of any size

with the CT scans will be considered in CR if PET negative) on the area of initial bulky

disease (see above for the definition of nodal and/or mediastinal bulk). Evaluation of the

initial extension of disease, as documented by CT scan before chemotherapy, will be

instrumental for planning the radiation fields. The irradiation should start within four weeks

after the end of the last chemotherapy course. For a detailed description of radiotherapy

guidelines of the protocol, see the Appendix M.

SALVAGE TREATMENT OF PET-2 POSITIVE PATIENTS Patients will be treated according to the IIL-HD0802 protocol that is summarised as

follows:

• PET-2 positive patients are candidate to receive 4 courses of IGEV salvage

chemotherapy.

IGEV is scheduled as summarised in appendix G.

The regimen will be supported by adequate anti-emetic and supportive treatment as

summarised in appendix L.

Lenograstim 5 μg/kg/die is planned from day 7 until the end of neutropenia (neutrophils

> 500/mm3) or the end of peripheral stem cell collection.

Peripheral stem cell are collected and harvested after the third course of IGEV (target

of 8x106/Kg CD34+ cells: for two autologous stem cell rescue with 4x106/Kg CD34+

cells each).

• Response is evaluated at the end of IGEV chemotherapy with CT and PET or CT/PET

(PET-IGEV) and subsequent treatment is planned according to PET-IGEV as follows:

• PET-IGEV negative patients: according to IIL-HD0802 protocol these patients will be

treated with high dose BEAM chemotherapy followed by autologous stem cell rescue.

High dose BEAM schedule is summarised in appendix H.

• PET-IGEV positive patients. Patients will be stratified according to the availability of a

HLA identical stem cell donor and they will be treated according to genetic selection as

follows:


18

- HLA identical donor available: autologous transplantation followed by reduced

induction conditioning (RIC) allogenic transplantation

o High dose melphalan chemotherapy, as summarised in appendix I, followed by

autologous stem cell rescue.

o Subsequent RIC allogenic transplantation according to the IIL-HD0802 salvage

protocol.

- Absence of a HLA identical donor: double autologous transplantation:

o High dose melphalan chemotherapy (appendix I) followed by autologous stem

cell rescue.

o Second autologous transplantation with BEAM chemotherapy (appendix H)

followed by autologous stem cell rescue.

PET EVALUATION PET scan will be performed and revised according to international guidelines on state of

the art PET cameras (30).

PET scans will be scored as negative or positive upon a central review ( see appendix R

for detailed information)

TOXICITY AND ADVERSE EVENTS EVALUATION Timely, accurate, and complete reporting and analysis of safety information from clinical

studies are crucial.

• Averse event definitions

- Adverse Event

An adverse event is any untoward medical occurrence in a clinical study subject

administered a pharmaceutical product. An adverse event does not necessarily

have a causal relationship with the treatment. An adverse event can therefore be

any unfavourable and unintended sign (including an abnormal laboratory finding),

symptom, or disease temporally associated with treatment.

- Serious Adverse Event (SAE)

A serious adverse event is any untoward medical occurrence that meets any of the

following conditions:

o results in death

o is life-threatening

o requires inpatient hospitalization or prolongation of existing hospitalization


19

o results in persistent or significant disability/incapacity, or

o is a congenital anomaly/birth defect

The cause of death of a subject in a clinical study, whether or not the event is

expected or associated with the investigational agent, is considered a serious

adverse event.

- Suspected Unexpected Serious Adverse Reaction (SUSAR)

An unlisted adverse event, the nature or severity of which is not consistent with the

applicable product information. For an investigational drug, the expectedness of an

adverse event will be determined by whether or not it is listed in the Investigator's

Brochure of experimental drug. For a drugs with a marketing authorization, the

expectedness of an adverse event will be determined by whether or not it is listed in

the summary of product characteristics (SmPC).

- Associated With the Use of the Drug

An adverse event is considered associated with the use of the drug if the attribution

is possible, probable, or very likely by the definitions listed in following section.

• Attribution Definitions

For both serious and non-serious adverse events, the Investigator must determine both

the intensity of the event and the relationship of the event to study drug administration.

- Intensity

for each adverse event will be determined by using Version 3.0 of the National

Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) as

a guideline, wherever possible; a copy of the NCI-CTCAE Version 3.0 can be

downloaded from the Cancer Therapy Evaluation Program (CTEP) home page

(http://ctep.cancer.gov/forms/CTCAEv3.pdf). In those cases where the NCI CTCAE

do not apply, intensity should be defined according to the following criteria:

1. Mild: awareness of sign or symptom, but easily tolerated

2. Moderate: discomfort enough to cause interference with normal daily activities

3. Severe: inability to perform normal daily activities

4. Life Threatening: immediate risk of death from the reaction as it occurred.

5. Fatal: death.

- Relationship to study drug administration will be determined as follows:

o Not related: an adverse event which is not related to the use of the drug.

o Unlikely/Doubtful: an adverse event for which an alternative explanation is more

likely, e.g., concomitant drug(s), concomitant disease(s), or the relationship in time

suggests that a causal relationship is unlikely.


20

o Possible: an adverse event which might be due to the use of the drug. An

alternative explanation, e.g., concomitant drug(s), concomitant disease(s), is

inconclusive. The relationship in time is reasonable; therefore, the causal

relationship cannot be excluded.

o Probable: an adverse event which might be due to the use of the drug. The

relationship in time is suggestive (e.g., confirmed by dechallenge). An alternative

explanation is less likely, e.g., concomitant drug(s), concomitant disease(s).

o Definite/Very Likely: an adverse event which is listed as a possible adverse

reaction and cannot be reasonably explained by an alternative explanation, e.g.,

concomitant drug(s), concomitant disease(s). The relationship in time is very

suggestive (e.g., it is confirmed by dechallenge and rechallenge).

o Not assessable: there is insufficient or incomplete evidence to make a clinical

judgement of the causal relationship.

a) Procedures

All SAE and SUSAR that occur between the first study-related procedure and 30 days

after the last dose of study drug will be reported. They must be recorded regardless of

or presumed relationship to study therapy, using medical terminology in the source

document and the CRF. Investigators must record in the CRF their opinion concerning

the relationship of the adverse event to study therapy. All measures required for

adverse event management must be recorded in the source document and reported

according to Investigator-Sponsor instructions.

All grade 3 and 4 adverse events, considered related, must be followed until resolution

of the event, or the event improves to a grade 2 or better.

All SAE and SUSAR occurring during clinical studies must be reported to the study

Sponsor (Fondazione IIL-ONLUS) by 24 hours of their knowledge of the event.

Information regarding SAE and SUSAR will be transmitted to the Sponsor using the

SAE form, which must be signed by a member of the investigational staff. The initial

report of a SAE or SUSAR must be reported by fax to the farmacovigilance IIL office of

Alessandria: Address: S.O.C. di Ematologia, Azienda Ospedaliera SS Antonio e Biagio, Alessandria. Via Venezia 18 – 15100 - Alessandria Telephone: 0039-0131-206262 Fax: 0039-0131-261029 E-mail: [email protected]

CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW UP


21

Clinical evaluation and laboratory tests at study entry, for evaluating response and during

follow up are summarize in appendix D.

STATISTICAL CONSIDERATIONS 1. Phase II study (PET-2 positive patients) a) Sample size

The primary end point for PET-2 positive patients shifted to the salvage with high dose

chemotherapy is the 2-year PFS rate. The 2-year PFS rate of PET-2 positive patients

treated with 6 courses of ABVD or other similar regimens is of only 10-15%. A salvage

rate with high dose chemotherapy of at least 35% is considered of clinical relevance.

The sample size of the study has been estimated according to the Fleming design,

assuming:

- Alpha error = 0.05

- Beta error = 0.05

- EFS0 (the maximum 2-year PFS achievable with standard treatments) = 0.15

- EFS1 (the minimum 2-year PFS expected with the high dose salvage therapy) =

0.35

The study requires 52 subjects to decide whether the 2-year PFS is less than or equal

to 15% or greater than or equal to 35%.

b) Statistical analyses

If the number of event-free patients is 13 or more, the hypothesis that the 2-year PFS

<= 15% is rejected with a target error rate of 0.05 and an actual error rate of 0.04. If

the number of event-free patients is 12 or less, the hypothesis that the 2-year PFS >=

35% is rejected with a target error rate of 0.05 and an actual error rate of 0.045.

Primary efficacy analyses will be carried out on PFS. All time to event endpoints will

be analysed with the Kaplan Meier method.

The proportion of complete remission (CR) and partial remission (PR), with 95%

confidence intervals, will be estimated on all enrolled patients.

Safety analyses will be based on patients actually treated and frequency of toxicities

will be reported by type, grade and number of cycles.

Explorative analyses of factors predicting response and toxicity will be carried out

using logistic regression models. Odds ratios (OR) and 95% confidence intervals will

be estimated for a set of potential predictors (age, stage, extra nodal disease, IPS,

ECOG).

2. Phase III study


22

a) Sample size

The primary end point for the phase III study, comparing radiotherapy vs no

radiotherapy in PET-2 negative patients, is the 2-year EFS.

The sample size of the study has been estimated assuming:

- Alpha error = 0.05

- Beta error = 0.20

- 2-year EFS in the arm with RT = 0.60

- 2-year EFS in the arm with no RT = 0.80

- Accrual period (constant) = 4 years

- Minimum follow up = 2 years

A two-sided log rank test with an overall sample size of 120 subjects (of which 60 are

in the RT arm and 60 are in the no-RT arm) achieves 80% power at a 0.05

significance level to detect a difference of 0.20 between 0.60 and 0.80 - the

proportions of event free patients at 2 years in each group.

b) Statistical analyses

A flow diagram, with the number of the patients through the trial (evaluated, enrolled,

randomised, treated and analysed) will be provided, according to the CONSORT

model.

Baseline characteristics of the patients will be analysed with descriptive statistics,

according to the type of variable: mean (standard deviation), median (percentiles) or

frequency (percentages).

Primary efficacy analyses will be carried out comparing EFS on the intent to treat

population randomised to RT or no-RT. All time to event endpoints will be analysed

with the Kaplan Meier method and groups compared with the logrank test.

To assess the presence of a strong interaction between RT and some clinical

characteristics, explorative subgroup analyses will be performed on patients stratified

by age, stage, extra nodal disease, IPS, ECOG. The Cox-proportional hazard

regression model, including interaction terms, will be used to estimate adjusted hazard

ratios (HR) and their precision (with 95% confidence intervals).

4. Overall sample size Taking into account the required sample size of the two studies (N=52 for the phase II

study on PET-2 positive patients and N=120 for the phase III study on PET-2 negative

patients with initial bulky disease or residual masses) the number of patients to be

enrolled at the diagnosis is about 300 because:


23

the proportion of PET-2 positive patients is expected to be about 20% (n=60

patients eligible for the phase II study);

out of the 240 PET-2 negative patients, about 55% (N=132) are expected to have

initial bulky disease or residual masses and are eligible for the phase III study.

5. Randomisation The enrolment and randomisation procedures will be implemented on a study specific

website. Patients with PET negative scan after six courses of ABVD will be stratified

according to baseline HL stage. Within each strata, patients will be randomised with a

ratio 1:1 with a block sequence.

STUDY DURATION The start of the study is planned for July 2008. All patients defined by inclusion criteria

should be included by participating centres. 300 patients from 50 Italian centres will be

enrolled. If the study is terminated prematurely, the reasons must be documented.

The last patient is expected to enter the study at the end of June 2012.

A minimum follow up of 12 months is required after the enrolment of the last PET-2

positive patient in order to calculate the actuarial progression free survival (PFS) of PET-2

positive group which is the main end point of the study. The final evaluation is therefore

foreseen for September 2013.

It is understood that these accrual rates are based on reasonable planning expectations.

The investigator should, however, continually compare the actual and expected accrual

rates, and make every effort to ensure that they are as closely matched as possible.


24

BIBLIOGRAPHY 1) De Vita VT et al. Combination chemotherapy in the treatment of advanced

Hodgkin’s disease. Ann Intern Med 73: 881-895; 1970 2) Longo DL et al. Twenty years of MOPP therapy for Hodgkin’s disease. J. Clin

Oncol. 4: 1295-1306; 1986 3) Santoro A et al. Prolomged diseade-free survival in MOPP-resistant Hodgkin’s

disease after treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). Cancer Chemother Pharamcol 2: 101-105; 1979

4) Canellos GP et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD or MOPP alternating with ABVD. New Engl. J Med 327: 1478-1484; 1992

5) Connors J Is cyclic chemotherapy better than stadard four-drug chemotherapy for Hodgkin’s disease ? Yes. Important Adv Oncol 189-195; 1993

6) Duggan DB et al Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an Intergroup trial. J. Clin. Oncol. 21: 607-614; 2003

7) Canellos GP, Niedzwiecki D. Long-term follow-up of Hodgkin’s disease trial. N. Engl. J Med 346: 1417-1418; 2002

8) Diehl et al. German Hodgkin’s Lymphoma Study Group. Standard and increase-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. New Engl. J Med. 348: 2386-2395; 2003

9) Gallamini A et al. The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin's disease. Hematologica 91(4):475-81; 2006

10) Hutchings M et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma.Blood 107(1):52-9; 2006

11) Gallamini A et al. Early interim FDG-PET overrules the prognostic role of IPS in advanced-stage Hodgkin lymphoma: a report from a joint Italo-Danish study. J Clin Oncol 25, 3746-3752, 2007.

12) Schmitz N et al. aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease. A randomised trial. Lancet 359, 2065-2071, 2002.

13) Bartlett NL. Therapies for relapsed Hodkin Lymphoma: transplant and non transplant approaches including immunotherapy. Hematology 245-251, 2005

14) Josting A et al. Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood 96, 1280-1286, 2000.

15) Ferme C et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Etude des Lymphomes de l’Adulte H89 trial. J Clin Oncol 20, 467-475, 2002.

16) Castagna L et al. Tandem high-dose chemotherapy and autologous stem cell transplantation in refractory/relapsed Hodgkin’s lymphoma: a monocenter prospective study. Am J Hematol 82, 122-127, 2007.

17) Carella AM et al. Autografting followed by nonmyeloablative immunosoppressive chemotherapy and allogenic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma.

18) Robinson SP et al. Chemoresistant or aggressive lymphoma predicts for a poor outcome following a reduced-intensity allogenic stem cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and


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Bone Marrow Transplantation. Blood 100, 4310-4316, 2002. J Clin Oncol 18, 3918-3924, 2000.

19) Balzarotti M et al. Factors affecting outcome of patients with refractory/relapsed Hodgkin’s disaes (HD) treated with IGEV chemotherapy (CT) and high dose consolidation therapy (HDT) with stem cell rescue. 47° ASH meeting Atlanta abst 2091.

20) Ferme C et al. Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Group d’Etudes des Lymphomes de l’Adulte (GELA). Blood 107, 4636-4642, 2006.

21) Brice P et al. Advanced Hodgkin disease with large mediastinal involvement can be treated with eigth cycles of chemotherapy alone after a major response to six cycles of chemotherapy. A study of 82 patients from the Group d’Etudes des Lymphomes de l’Adulte H89 trial. Cancer 92, 453-459, 2001.

22) Aleman BMP et al. Involved field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med 348, 2396-2406, 2003.

23) Aleman BM et al. Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 67, 19-30, 2007.

24) Engert E et al. H12 randomised trial comparing 8 dose-escalated cycles of BEACOPP with 4 escaleted and 4 baseline cycles in patients with advanced stage Hodgkin lymphoma (HL): an analysis of the German Hodgkin Lymphoma Study Group (GSHG). ASH 2006 abst 99.

25) Laskar S et al. Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need ? J Clin Oncol 22, 62-68, 2004.

26) Re A et al. Late computed tomography scan response improvement and gallium scintigraphy evaluation as on-treatment prognostic parameters to tailor treatment intensity in patients with Hodgkin’s lymphoma. A prospective phase II study. Ann Oncol 2008, DOI: 10.1093/annonc/mdm596.

27) Cheson BD et al. Revised response criteria for malignant lymphoma. J Clin Oncol 25, 579-586, 2007.

28) Lister TA et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7, 1630-1636, 1989.

29) Horning S et al. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 20, 630, 2002.

30) Brepoels L. et al. Hodgkin lymphoma: Response assessement by Revised International Workshop Criteria. Leukemia & Lymphoma 48,1539-1547, 2007

31) Yahalom et al. The involved field id back: issues in delineating thew radiation field in Hodgkin’s disease. Ann Oncol. 13 (S1), 79-83, 2002.

APPENDIX A. Study flow chart


26

+

random

Advanced stage Hodgkin lymphoma

IIL-HD0801 protocolstage IIB-IV

Staging including CT and PET scan or CTPET

2 ABVD

- PET

2 ABVDCT scan optional

salvage2 ABVD

- CT + PET +

Rt bulky No Rt

Appendix B. Flow chart of salvage therapy for PET-2 positive patients (more details in the IIL HD0802 protocol)


27

+PET-

BEAM

PET-2 positive

4 IGEV

PAM

donor

Salvage program of PET2 + patients (IIL-HD0802 protocol)

Peripheral stem cell harvesting after 3° IGEV

HLA- HLA+

PAM

BEAM allo RIC


28

APPENDIX C. Enrolment and randomization procedures

Patients will be registered in the study via web site the end of their staging, before

beginning the first course of ABVD.

Both enrolment and randomization will be centralized via online procedure procedures

from Epidemiologia dei Tumori – università e ASO San Giovanni Battista - Torino through

the Epiclin web site (http://www.epiclin.cpo.it). Responsible for randomization

procedures and data collection is dr. Giovannino Ciccone (tel 011-6336857).

At the end of the second course of ABVD, PET-2 imaging will be sent to the central review

nuclear medicine panel ( see Appendix S ) and and patients will be categorized as PET-2

negative or positive according to the judgement of the panel (cfr appendix R). PET-2

negative patients will be treated with 4 more courses of ABVD, and at the end of a total of

6 courses of ABVD they will be randomized between stop of treatment and radiotherapy

on bulky areas.

PET-2 positive patients will be homogeneously treated according to the high dose IIL-

HD0802 salvage protocol.

http://www.epiclin.cpo.it/


29

APPENDIX D. Summary table of required investigations.

APPENDIX D1: The first phase of treatment for all patients

baseline Before each corse of

chemotherapy (every 15 days)

After the 2° ABVD

Medical history + PS (ECOG) + + + Visit + + + ECG + Measurement of all palpable nodes

+ + +

Heigth and weigth + + Cell blood count + + + ESR + + Viral markers : HIV, HBV, HCV + Serum chemistry (AST, ALT, bilirubine, creatinine, LDH, serum albumin, ecc)

+ + +

CT scan (neck, thorax, abdomen)

+

FDG-PET scan + + Monolateral bone marrow biopsy

+

Serum sample freeze + + Ventricula ejection fraction + Respiratory function + Sperm criopreservation + LH, FHS, oestradiol, testosteron, FT3, FT4, TSH

+


30

APPENDIX D2: The second phase of treatment for PET-2 negative patients

Before each

corse of chemotherapy (every 15 days)

After the 4° ABVD

After the 6° ABVD

3 months after the end of

radiotherapy (if done)

1 and 2 years after the end of the treatment

plan PS (ECOG) + + + + + Visit + + + + + Measurement of all palpable nodes

+ + + + +

Weigth + + + + + Cell blood count + + + + + ESR + + + + Serum chemistry (AST, ALT, bilirubine, creatinine, LDH, ecc)

+ + + + +

CT scan (neck, thorax and abdomen))

+ (optional and

limited to initial positive sites)

+ + +

FDG-PET scan + + Bilateral bone marrow biopsy +

(if positive at diagnosis)

Serum sample freeze + Ventricular ejection fraction + + + Respiratory function + + + Sperm criopreservation LH, FHS, oestradiol, testosteron, FT3, FT4, TSH

+

Quality of life + +


31

APPENDIX D3: The second phase of treatment for PET-2 positive patients

Before each

cuorse of IGEV

After the 4° IGEV

After the 1° ASCT

After the 2° ASCT or RIC

allogenic transplant

Every 4 months after

the end of the

treatment

1 and 2 years after the end of

the treatment

PS (ECOG) + + + + + + Visit + + + + + + ECG Measurement of all palpable nodes

+ + + + + +

Weigth + + + + + + Cell blood count + + + + + + ESR + + + + Serum chemistry (AST, ALT, bilirubine, creatinine, LDH, ecc)

+ + + + + +

CT scan (neck, thorax, abdomen)

+ + + +

FDG-PET scan + + + Bone marrow biopsy +(if + at the

beginning)

Serum sample freeze Ventricular ejection fraction

+ +

Respiratory function + + Sperm criopreservation LH, FHS, oestradiol, testosteron, FT3, FT4, TSH

+

Quality of life + + + +


32

Appendix E. ECOG performance status

Grade Description

0 Fully active, able to carry all pre-disease activities without restriction (Karnofsky 90-100).

1 Restrictred in physically strenuous activity but ambulatory and able to carry out

work of a light or sedentary nature (Karnosfky 70-80).

2 Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours (Karnofsky 50-60).

3 Capable of only limited self care, confined to bed or chair more than 50% of

waking hours (Karnofsky 30-40).

4 Completely disabled. Cannot carry on any self care. Totally confined to bed or chair (Karnofsky 10-20).

5 Dead.


33

Appendix F. ABVD chemotherapy

ABVD Drug dose days

mg/m2 1 15 Doxorubicin 25 i.v. * * Bleomycin 10 i.v. * * Vinblastine 6 i.v. * * Dacarbazine 375 i.v. * * Every 28 days

Dose reductions for hematological toxicity Absolute neutrophils

count (ANC) Platelets % Drugs

> 1.500 >100.000 100 % 1.499-1.000 99-70 100 % Blm,

66 % Adm, Vbl,Dcz < 1.000 <70 withdrawn 1 week

The regimen will be supported by an adequate anti-emetic and supportive treatment as



34

Appendix G. IGEV salvage chemotherapy

IGEV Drugs dose Days

1 2 3 4 Ifosfamide 2000 mg/mq i.v. * * * * Mesna uroprotection 600 mg/mq x 3 i.v. * * * * Gemcitabine 800 mg/mq i.v. * - - * Vinorelbine 20 mg/mq i.v. * - - - Prednisolone 100 mg tot. i.v * * * * Every 21 days Lenograstim 5 μg/kg/die is planned from day 7 until the end of neutropenia (neutrophils > 500/mm3) or the end of peripheral stem cell collection.

The regimen will be supported by an adequate anti-emetic and supportive treatment as


Dose reductions and/or delay for hematological toxicity:

- Before each course, if at day 21 absolute neutrophils count (ANC) <1500/mm3 and/or

platelets <100.000/mm3, the whole regimen will be delayed by one week.

- If at day 28 the ANC is >1000-1500/ mm3 and/or PLT 75-100.000/ mm3 the dosage of

each chemotherapeutic drug will be reduced at 75%. If blood count has not recovered,

one further delay-week is admitted.

- If at day 35 ANC are still <1000/mm3, and/or platelets < 75.000 mm3, the patient will go

off-study.


35

Appendix H: BEAM chemotherapy time Drugs 8.30 Navoban 1 f fisiol 100cc

9.00 CARMUSTINE ( 300mg/m2 ) gluc 500cc (1h ) === === === === === ===

9.00 Urbason 10 mg === ===

9.00 ETOPOSIDE ( 100 mg/m2 ) fisiol 500cc (1h) === === ===

10.00 ARA-C ( 200 mg/m2) fisiol 500cc (3h) === === ===

9.00 MELPHALAN ( 70 mg/m2) fisiol 100cc (30’) === === === === === ===

11.00 MELPHALAN (70 mg/m2) fisiol 100cc (30’) === === === === === ===

14 Navoban 1 f fisiol 100cc ===

20.30 Navoban 1 f fisiol 100 cc

Urbason 10 mg === === ===

21.00 ETOPOSIDE ( 100 mg/m2 ) fisiol 500cc(1h) === === ===

22.00 ARA-C ( 200 mg/ m2) fisiol 500cc (3h) === === ===

infusione continua nelle 24 h. Fisiol 500cc+ NaHCO3 30 mEq Alternato a Glucosata 5% 500cc + Kcl 20 mEq

125 cc/h

100cc/h

100cc/h

100cc/h

100cc/h

125 cc/h

125 cc/h

Reinfusione di cellule staminali === === === === === ===


36

Appendix I: HIGH DOSE MELPHALAN Time Drugs 8.00 Navoban 1 f fisiol 100 cc === === ===

Urbason 125 mg fisiol 100 cc === === === === ===

Mepral 1 f fisiol 100cc === === === === ===

9.00 MELPHALAN (70/mq) fisiol 100 cc (30’) === === === === === ===



14.00 Navoban 1 f fisol 100 cc === === === === === ===

21.00 Navoban 1 f fisol 100 cc === === === ===

infusione continua nelle 24 h.

Fisiol 500cc+ NaHCO3 30 mEq Alternato a

Glucosata 5% 500cc + Kcl 20 mEq

160 cc/h

160 cc/h

160 cc/h

160cc/h

125 cc/h

125 cc/h

125 cc/h

Reinfusione di cellule staminali === === === === === ===


37

Appendix L. Anti-emetic and supportive treatment. • Anti-bacterial and anti-fungal prophylaxis

- For ABVD: specific anti-bacteria and anti-mycosis prophylaxis are not foreseen. - For IGEV: chinolone and fluconazole or itraconazole prophylaxis are considered

during neutropenic phases according to individual centre policies. - For autologous and allogenic stem cell transplantation: co-trimoxazole or

pentamidine, chinolone prophylaxis, acyclovir and anti-mycosis prophylaxis will be scheduled according to the specific IIL-HD0802 high dose protocol.

• Anti-viral prophylaxis - For HCV + patients: AST, ALT, ALP and bilirubine will be monitored before each

new course of chemotherapy and at least every three weeks. Quantitative HCV RNA will be monitored at least once a year.

- For HBV+ (anti-HBc+, antiHBs±)ABVD: lamivudine 100 mg/die will be administered from the start of treatment until at least six months after the end of treatment. AST, ALT, ALP and bilirubine will be monitored before each new course of chemotherapy and at least every three weeks. HBV DNA will be monitored at least once a year.

- For CMV during high dose treatment: CMV will be monitored and anti-CMV therapy will be performed according to the specific IIL-HD0802 high dose protocol.

• Anti-emetic treatment - For ABVD: single i.v. infusion (bolus over 30 seconds) of palonosetron 250 μg is

adminstered 30 min before chemotherapy. - For IGEV: ondansetron, tropisetron, granisetron (according to indivudal centre

policy) once or twice a day for 4 consecutive days or more as needed for individual patient.

- For autologous and allogenic stem cell transplantation: it will be scheduled according to the specific IIL-HD0802 high dose protocol.

• Granulocyte growth factors - For ABVD: lenograstim 5 μg/kg/die is used on demand only when neutropenia

(neutrophils < 500/mm3) with or without infections is present until the end of neutropenia (neutrophils < 500/mm3).

- For IGEV: lenograstim 5 μg/kg/die is planned from day 7 until the end of neutropenia (neutrophils > 500/mm3) or the end of peripheral stem cell collection.

- For autologous and allogenic stem cell transplantation: G-CSF treatment will be scheduled according to the specific IIL-HD0802 high dose protocol.

• Transfusional support - Packed red cell transfusion: when Hb<8/dl. - Platelet transfusion: when plts <10 x 109/l or < 20 x 109/l in presence of fever

end/or infection. • Erythropoiesis stimulating agents (ESA)

ESA treatment is recommended when Hb < 10 gr/dl according to ASCO-ASH international guidelines (Rizzo JD et al JCO 26, 132-149, 2008).


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Appendix M. Radiotherapy Guidelines

In this protocol, radiation therapy will be delivered as consolidation treatment in CR patients (PET2 negative patients) at the end of chemotherapy courses on initial bulky disease areas. Bulky disease is defined as a mass of at least 5 cm (largest diameter) or a bulky mediastinum (a ratio of the mediastinum to the thorax of at least 0.35 at the level of T5 through T6 at the chest X-ray). Initial bulky disease, regardless of its site, will be treated with the involved-field concept (IF-RT). From this point of view, according to the IF guidelines published by Yahalom (30), we distinguish the following IF regions:

o neck (unilateral, with supraclavicular) o mediastinum (plus hilar regions) o axilla (infra- and supraclavicular) o spleen o para-aortic o inguinal (femoral and iliac)

For all of these regions, radiation fields definitions are mainly based on anatomical structures (bony landmarks), at least for 2D-RT, according to the following consensus guidelines (30): a) Unilateral cervical/supraclavicular region

Involvement at any cervical level with or without involvement of the supraclavicular (SLC) nodes. - Upper border

1-2 cm above the lower tip of the mastoid process and mid-point through the chin. - Lower border

2 cm below the bottom of the clavicle. - Lateral border

To include the medial 2/3 of the clavicle. - Medial border

If the supraclavicular nodes are not involved, place the border at the ipsilateral transverse processes, except when medial nodes close to the vertebral bodies are seen on the initial staging neck CT scan. For the medial nodes include the entire vertebral body. When the supraclavicular nodes are involved, the border should be placed at the controlateral trasverse processes.

b) Bilateral cervical/ supraclavicular region

Treat both cervical and supraclavicular regions as described above regardless of the extent of disease on each side. Use a posterior mouth block if treating the patient supine to block the upper field divergence through the mouth.

c) Mediastinum

Involvement of the mediastinum and/or the hilar nodes.. - Upper border

C7-T1 interspace. - Lower border

The lower of 5 cm below the carina or 2 cm below the pre-chemotherapy inferior border.


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- Lateral border The post-chemotherapy volume with 1.5 cm margin.

- Hilar area To be included with 1 cm margin

d) Axillay region

The ipsilateral axillary, infraclavicular and supraclavicular areas are treated when the axillla is involved. Whenever possible use CT- based planning for this region. - Upper border

C5-C6 interspace - Lower border

The lower of (i) the tip of the scapula or (ii) 2 cm below the lowest axillary node. - Medial border

Ipsilateral cervical trasverse process. Include the vertebral bodies only if the SCL are involved.

- Lateral border Flash axilla

e) Spleen

The spleen is treated only if abnormal imaging was suggestive of massive involvement. The post-chemotherapy volume is treated with 1.5 cm margins. The left kidney should be outlined on the plan/film. CT- based planning should be used.

f) Abdomen (para-aortic nodes)

- Upper border Top of T11 and at least 2 cm above pre-chemotherapy volume.

- Lower border Bottom of L4 and at least 2 cm below pre-chemotherapy volume.

- Lateral borders The edge of the transverse processes and least 2 cm from the post-chemotherapy volume.

Note The kidneys should be outlined and considered when designing the blocks. The porta-hepatis region should be included if originally involved (this should be identified with CT-based planning).

g) Inguinal/femoral/external iliac region

These ipsilateral lymph node groups are treated together if any of the nodes are involved. - Upper border

Middle of the sacro-iliac joint. - Lower border

5 cm below the lesser trochanter. - Lateral border

The greater trochanter and 2 cm lateral to initially incolved nodes. - Medial border

Medial border of the obturator foramen with al least 2 cm medial to involved nodes The general concept, expecially in terms of 3D-RT, is to adapt radiation fields as a best compromise between pre- and post-chemotherapy volume and sites.


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In this protocol, patients with residual disease of any size visible on CT scans will be considered in CR if PET2 and PET6 negative. The different pattern of morphologic response could be of value in drawing radiation fields. Since majority of bulky disease areas will be represented by medastinal disease, and since the most significant late toxicity will be related to mediastinal irradiation (heart, lung tissue), the need of taking into account the response to chemotherapy is particularly important in consolidation mediastinal irradiation. For example, the lateral borders of mediastinal fields should specifically take into account the post-chemotherapy volume, while the length of mediastinal fields will be planned according to the pre-chemotherapy volume, in order to better cover all different mediastinal nodes. Patients must be treated with high energy photons (range 5-18 MeV). All patients will be planned on CT-scans, considering both pre- and post-chemotherapy volume. The choice of energy, as well as the optimal technical approach (2D-RT, 3D-RT, beams’ arrangement) will depend on the different initial bulky area and will be made on an individual basis (consolidation radiotherapy on the axilla is obviously very different from consolidation mediastinal irradiation; consolidation mediastinal irradiation of a very large bulky disease is different in case of no residual disease on CT scan compared to residual disease even if PET-negative). All different radiation fields should be customized (cerrobend blocks or MLC), in order to spare as much as possible healthy tissue from radiation beams. Portal imaging has to be periodically evaluated to carefully check patients’ setup. Concerning radiation doses, since all patients will be in CR status when receiving radiotherapy, 30.6 Gy will be delivered in 17 daily fractions of 1.8 Gy. Radiation doses will be specified according to ICRU62 rules.


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Appendix N Codice sperimentazione IIL-HD0801 Titolo dello studio: “Salvataggio precoce con chemioterapia ad alte dosi e trapianto di cellule staminali nel linfoma di Hodgkin con PET positiva dopo i primi 2 cicli di chemioterapia ABVD e confronto, nei casi PET-2 negativi trattati con 6 ABVD, di consolidamento con radioterapia sulle aree bulky verso sospensione della terapia”. Caro collega, il tuo paziente partecipa ad uno studio clinico multicentrico randomizzato promosso dall’Intergruppo Italiano Linfomi (IIL) sul linfoma di Hodgkin. Lo studio riguarda i pazienti in stadio avanzato (IIB-IV) trattati con chemioterapia convenzionale ABVD e persegue i due seguenti obiettivi: 1. Valutare se i casi con positività residua alla PET dopo i primi 2 cicli ABVD, che sono

casi a cattiva prognosi, beneficiano di uno shift precoce a chemioterapia di salvataggio ad alte dosi con supporto di cellule staminali.

2. Valutare se i casi PET negativi dopo i primi 2 cicli di chemioterapia ABVD, che sono casi a buona prognosi, possono risparmiare la radioterapia sull’area bulky dopo aver terminato il loro programma di 6 cicli ABVD.

La prognosi del linfoma di Hodgkin in stadio avanzato (IIB-IV) è solo modicamente migliorata negli ultimi anni. Pur essendo possibile guarire con la chemioterapia un’elevata percentuale di casi, rimane purtroppo un gruppo non indifferente di pazienti che non riescono ad andare in remissione o recidivano dopo 6-8 cicli di chemioterapia ABVD. Negli ultimi anni il gruppo cooperativo tedesco ha dimostrato la superiorità di un ciclo chiamato “BEACOPP-intensificato” nei confronti del tradizionale ABVD. Si tratta tuttavia di uno schema molto più aggressivo dell’ABVD caratterizzato da superiore tossicità immediata e tardiva. Trattare quindi tutti gli stadi avanzati con questo nuovo schema comporta un incremento di tossicità, presumibilmente immotivata, per un’elevata quota di pazienti. I fattori prognostici tradizionali non consentono purtroppo di prevedere quali siano i pazienti a prognosi peggiore, onde riservare solo a loro fin dalla diagnosi un trattamento più aggressivo e trattare tutti gli altri con il ciclo ABVD meno aggressivo. Recentemente è però emerso un nuovo fattore prognostico di grande rilievo. Si tratta della valutazione della risposta effettuata dopo i primi 2 cicli di chemioterapia ABVD con tomografia ad emissione di positroni con fluoro-desossi-glucosio (PET). La PET funziona come test di chemiosensibilità della malattia e si è rivelata utilissima. Si è visto che i pazienti che dopo i primi 2 cicli presentano una negativizzazione della PET nelle aree inizialmente positive hanno un’ottima prognosi. Sono praticamente tutti in remissione completa al termine dei 6 cicli di ABVD e quasi nessuno di loro è candidato a recidivare. Al contrario i pazienti che al termine del 2° ABVD dimostrano ancora una positività della PET non riescono a ottenere la remissione con gli altri successivi 4 cicli di ABVD o recidivano precocemente e non più del 15-20% ottiene la guarigione definitiva. Sembra quindi razionale modulare la terapia dei pazienti di Hodgkin in stadio avanzato sulla base della risposta precoce ottenuta dopo i primi 2 cicli ABVD e valutata con la PET. In questo modo tutti i pazienti possono iniziare una terapia non troppo aggressiva come l’ABVD. I soggetti responsivi (PET-2 negativi) possono poi proseguire il loro trattamento


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convenzionale con ABVD con ottima probabilità di guarigione. I soggetti non responsivi (PET-2 ancora positivi) dovrebbero invece beneficiare di una terapia di salvataggio precoce intensificata che prevede le alte dosi di farmaci supportate da trapianto di cellule staminali. Lo studio attuale si basa sul fatto che il miglior salvataggio per il linfoma di Hodgkin è la terapia ad alte dosi con supporto di celle staminali autologhe e sul fatto che nei casi in cui neppure l’autotrapianto funziona vi sono esperienze positive con il trapianto allogenico da donatore sano. Nei casi a prognosi favorevoli uno dei quesiti ancora aperti è invece capire se, dopo aver ottenuto la remissione completa con la chemioterapia, è veramente indispensabile la radioterapia sulle aree coinvolte inizialmente da adenopatie di grandi dimensioni (bulky). Questa prassi, utilizzata fino ai nostri giorni, comporta infatti un rischio di tossicità tardiva non indifferente e vi sono già dati che suggeriscono che potrebbe essere eliminata senza aumento del rischio di recidiva. Lo studio IIL-HD0801 prevede l’esecuzione di una PET basale, prima dell’inizio di ogni terapia, per i tutti pazienti arruolati con linfoma di Hodgkin in stadio avanzato. Essi saranno poi trattati con 2 cicli convenzionali di ABVD e al termine del 2° ciclo verrà ripetuta una seconda PET per valutare la risposta precoce al trattamento. Sulla base di questa seconda PET i pazienti saranno suddivisi nei 2 seguenti gruppi: a) PET-2 negativi a buona prognosi; b) PET-2 positivi a cattiva prognosi. La successiva terapia sarà quindi modulata come segue: 1. Casi PET-2 negativi a buona prognosi:

Prosecuzione della terapia non aggressiva con ABVD per altri 4 cicli fino al raggiungimento di 6 cicli in totale. Tutti i casi senza localizzazione bulky iniziale termineranno il loro trattamento dopo i 6 cicli e inizieranno il follow up. I casi che all’inizio presentavano localizzazioni bulky sono invece randomizzati tra:

a. Stop del trattamento al termine dei 6 cicli. b. Radioterapia ulteriore di consolidamento sull’area inizialmente coinvolta da

localizzazione bulky. 2. Casi PET-2 positivi a cattiva prognosi:

Prosecuzione con un immediato passaggio a terapia aggressiva di salvataggio secondo un altro protocollo di terapia (IIL-HD0802) che in sintesi pianifica:

a. 4 cicli di salvataggio IGEV (ifosfamide, gemcitabina e vinorelbina), già usato con successo come salvataggio del linfoma di Hodgkin, con reclutamento e congelamento di cellule staminali autologhe dopo il 3° ciclo.

b. Ripetizione della PET al termine del 4° IGEV per valutare se è stata ottenuta la remissione (negatività PET).

c. Sulla base della PET effettuata dopo 4 IGEV la terapia prosegue nel modo seguente: - Casi PET negativi dopo IGEV: consolidamento con un solo autotrapianto di

cellule staminali (condizionato con lo schema convenzionale BEAM). - Casi PET positivi dopo IGEV: consolidamento con un autotrapianto

(condizionato con lo schema melphalan ad alte dosi) seguito da un successivo trapianto allogenico non mieloablativo se vi è la disponibilità di un donatore HLA compatibile. Nel caso in cui non esista un donatore HLA compatibile si procederà a un secondo autotrapianto (condizionato con lo schema convenzionale BEAM).


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Gli studi PET saranno valutati da un gruppo di esperti medici nucleari: in caso di disaccordo con quello dello specialista che ha effettuato l’esame PET, il giudizio del gruppo di esperti, preso a maggioranza, sarà quello valido alla fine del presente protocollo. Gli effetti collaterali che possono insorgere per i diversi schemi di chemioterapia sono principalmente: nausea, vomito, astenia, alopecia, mucosite con dolore alla bocca o allo stomaco, alterazioni dell’alvo e pancitopenia. Gli schemi di chemioterapia ad alte dosi con autotrapianto provocano una vera e propria fase di aplasia midollare. In tale periodo il suo paziente sarà ricoverato e tenuto sotto stretta osservazione, dovrà eseguire terapie con fattori di crescita e, quando necessario, dovrà ricevere un supporto trasfusionale. Il rischio di mortalità legato all’aplasia da trapianto autologo, se effettuato in centri adeguati, è omai minimo e non supera anche nelle peggiori casistiche il 5%. I pochi pazienti che dovranno essere sottoposti a trapianto allogenico non mieloablativo correranno soprattutto i rischi legati alla GVHD (reazione del trapianto contro l’ospite). Per un periodo prolungato si renderà necessaria terapia immunosoppressiva. Oltre agli effetti indotti direttamente dalla GVHD su vari organi e in particolare su cute, fegato, intestino e polmone, è facile che si attivino infezioni virali (es citomegalovirus, herpes zoster, Ebstein Barr ecc), micotiche o da altri germi opportunistici (es. pneumocistis Carinii) legate all’importante terapia immunosoppressiva. La mortalità globale del trapianto allogenico secondaria a queste complicanze varia con l’età dei pazienti, ma non è in ogni caso indifferente e a seconda delle casistiche si può aggirare sul 15-20%. Per ridurre l’incidenza delle complicanze infettive è previsto l’impiego di un’adeguata terapia antibiotica di profilassi e, se necessario, di un supporto con immunoglobuline endovena. Sono previsti quattro anni per arruolare 300 pazienti (240 nel gruppo PET-2 negativi e 60 nel gruppo PET-2 positivi) e un tempo ulteriore di follow-up di due anni dalla registrazione dell’ultimo paziente; la durata totale dello studio è, pertanto, di sei anni. La partecipazione allo studio del soggetto è completamente volontaria. Il paziente può rifiutare di partecipare allo studio o può decidere di uscire dallo studio stesso in qualsiasi momento, senza che questo possa riflettersi in alcun modo sul livello di assistenza medica a cui ha diritto. La partecipazione allo studio può essere altresì interrotta in qualsiasi momento senza il consenso del paziente, in seguito a richiesta da parte delle Autorità Regolatorie, del proponente (Intergruppo Italiano Linfomi, IIL) o del medico responsabile dello studio presso il centro in cui viene trattato il paziente. Restando a disposizione per eventuali chiarimenti, invio cordiali saluti. Dr_______________________________


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Appendix O

Codice sperimentazione IIL-HD0801

Titolo dello studio: “Salvataggio precoce con chemioterapia ad alte dosi e trapianto di cellule staminali nel linfoma di Hodgkin con PET positiva dopo i primi 2 cicli di chemioterapia ABVD e paragone, nei casi PET-2 negativi trattati con 6 ABVD, di consolidamento con radioterapia sulle aree bulky verso sospensione della terapia”. Caro Sig………………………………. La patologia da cui è affetto si chiama linfoma di Hodgkin. Si tratta di una delle tante forme di linfoma che risulta molto sensibile alla chemioterapia e alla radioterapia e può essere curata e guarita con questi strumenti in una elevata percentuale di casi. Nel suo caso il linfoma è presente in una forma abbastanza estesa classificato come stadio avanzato secondo il sistema di stadiazione usato. Questo non vuol dire che sia difficile da curare, ma significa semplicemente che sono coinvolte più sedi linfonodali e che per guarirlo è indispensabile utilizzare schemi di chemioterapia citostatica di una certa durata e aggressività. Purtroppo non è ancora possibile guarire con sicurezza tutti i pazienti. Sono infatti stati ottenuti ottimi successi già da molto tempo con il ciclo di chemioterapia convenzionale chiamato ABVD, ma la prognosi del linfoma di Hodgkin in stadio avanzato (IIB-IV) è solo modicamente migliorata negli ultimi anni. Pur essendo possibile guarire con la chemioterapia ABVD un’elevata percentuale di casi, rimane purtroppo un gruppo non indifferente di pazienti che non riescono ad andare in remissione o recidivano dopo 6-8 cicli. Negli ultimi anni il gruppo cooperativo tedesco ha dimostrato la maggiore efficacia di un ciclo chiamato “BEACOPP-intensificato” nei confronti del tradizionale ABVD. Si tratta tuttavia di uno schema molto più aggressivo dell’ABVD caratterizzato da superiore tossicità immediata e tardiva. Trattare quindi tutti gli stadi avanzati con questo nuovo schema comporta un incremento di tossicità, presumibilmente immotivata, per un’elevata quota di pazienti. I fattori prognostici tradizionali non consentono purtroppo di prevedere quali siano i pazienti a prognosi peggiore, onde riservare solo a loro fin dalla diagnosi un trattamento più aggressivo e trattare tutti gli altri con il ciclo ABVD meno aggressivo. Recentemente è però emerso un nuovo fattore prognostico di grande rilievo. Si tratta della valutazione della risposta effettuata dopo i primi 2 cicli di chemioterapia ABVD con un esame di medicina nucleare: la tomografia ad emissione di positroni con fluoro-desossi-glucosio (PET). Si tratta di un esame di medicina nucleare effettuato dopo iniezione endovenosa di un tracciante radioattivo che si accumula nei linfonodi colpiti dal linfoma e può essere fotografato dall’esterno con un apparecchio simile ad una TC che registra le radiazioni emesse dal tracciante. Questa indagine non è traumatica né invasiva: la dose di esposizione alle radiazioni è simile a quella della TC. Se eseguita dopo 2 cicli ABVD funziona come test di chemiosensibilità della malattia e si è rivelata utilissima. Si è visto che i pazienti che dopo i primi 2 cicli presentano una negativizzazione della PET nelle aree inizialmente positive hanno un’ottima prognosi. Sono praticamente tutti in remissione completa al termine dei 6 cicli di ABVD e quasi nessuno di loro è candidato a recidivare. Al


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contrario i pochi pazienti che al termine del 2° ABVD dimostrano ancora una positività della PET non riescono a ottenere la remissione con gli altri successivi 4 cicli di ABVD o recidivano precocemente e non più del 15-20% ottiene la guarigione definitiva. E’ quindi razionale modulare la terapia dei pazienti affetti da linfoma di Hodgkin in stadio avanzato sulla base della risposta precoce ottenuta dopo i primi 2 cicli ABVD valutata con la PET. In questo modo tutti i pazienti possono iniziare una terapia non troppo aggressiva come l’ABVD. I soggetti responsivi (PET-2 negativi) possono poi proseguire il loro trattamento convenzionale con ABVD con ottima probabilità di guarigione. I soggetti non responsivi (PET-2 ancora positivi) dovrebbero invece beneficiare di una terapia di salvataggio precoce intensificata che prevede le alte dosi di farmaci supportate da trapianto di cellule staminali. Con la presente, Le viene proposto di partecipare a uno studio multicentrico dell’Intergruppo Italiano Linfomi (IIL) condotto in Italia sui pazienti con linfoma di Hodgkin in stadio avanzato (stadio IIB-IV). Dopo i primi 2 cicli di terapia convenzionale ABVD lo studio si prefigge i due seguenti obiettivi: 1. Valutare se i casi con positività residua alla PET dopo i primi 2 cicli ABVD, che sono

casi a cattiva prognosi, beneficiano del passaggio immediato a una chemioterapia di salvataggio ad alte dosi con supporto di cellule staminali.

2. Valutare se i casi PET negativi dopo i primi 2 cicli di chemioterapia ABVD, che sono casi a buona prognosi, possono risparmiare la radioterapia sulle aree che erano inizialmente invase da adenopatie molto voluminose (bulky) dopo aver terminato il loro programma di 6 cicli ABVD.

Lo studio attuale si basa sul fatto che il miglior salvataggio per il linfoma di Hodgkin è la terapia ad alte dosi con supporto di celle staminali autologhe (autotrapianto) e sul fatto che nei casi in cui neppure l’autotrapianto funziona vi sono esperienze positive con il trapianto allogenico da donatore sano. Il trapianto allogenico è simile all’autotrapianto, ma in questo caso le cellule staminali non sono le proprie, ma quelle donate da un donatore volontario sano. Nei casi a prognosi favorevoli uno dei quesiti ancora aperti è invece capire se, dopo aver ottenuto la remissione completa con la chemioterapia, è veramente indispensabile la radioterapia sulle aree coinvolte inizialmente da adenopatie di grandi dimensioni (bulky). Questa prassi, utilizzata fino ai nostri giorni, comporta infatti un rischio di tossicità tardiva non indifferente e vi sono già dati che suggeriscono che potrebbe essere eliminata senza aumento del rischio di recidiva. Lo studio IIL-HD0801 prevede l’esecuzione di una PET basale, prima dell’inizio di ogni terapia. Questo tipo di esame fa comunque parte delle procedure di stadiazione alla diagnosi. I pazienti saranno poi trattati con 2 cicli convenzionali di ABVD e al termine del 2° ciclo verrà ripetuta una seconda PET per valutare la risposta precoce al trattamento. Sulla base di questa seconda PET i pazienti saranno suddivisi nei 2 seguenti gruppi: a) PET-2 negativi a buona prognosi; b) PET-2 positivi a cattiva prognosi. La successiva terapia sarà quindi modulata come segue: 1. Casi PET-2 negativi a buona prognosi:

Prosecuzione della terapia non aggressiva con ABVD per altri 4 cicli fino al raggiungimento di 6 cicli in totale. Tutti i casi senza localizzazioni iniziali voluminose


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termineranno il loro trattamento dopo i 6 cicli e poi faranno solo più le visite e gli esami di controllo. I casi che all’inizio presentavano localizzazioni voluminose sono invece suddivisi in modo casuale (randomizzati) tra i due seguenti comportamenti:

a. Stop del trattamento al termine dei 6 cicli. b. Radioterapia ulteriore di consolidamento sull’area inizialmente coinvolta da

localizzazioni voluminose. 2. Casi PET-2 positivi a cattiva prognosi:

Interruzione della terapia con ABVD e prosecuzione con un immediato passaggio a una terapia aggressiva di salvataggio precoce secondo un altro protocollo di terapia (IIL-HD0802) che in sintesi pianifica la seguente terapia:

a. 4 cicli di un altro ciclo più aggressivo chiamato IGEV (ifosfamide, gemcitabina e vinorelbina), già usato con successo come salvataggio del linfoma di Hodgkin, con reclutamento e congelamento di cellule staminali periferiche autologhe. Dopo il ciclo vi sarà una fase di alcuni giorni discesa dei globuli bianchi con riduzione delle difese e potenziale rischio infettivo. In questa fase sarà giornalmente iniettata sottocute una fiala di fattore di crescita chiamato G-CSF che serve a stimolare il midollo e facilitare la salita dei globuli bianchi. Nel momento in cui i globuli bianchi risalgono, circolano nel sangue le cellule staminali periferiche che possono essere raccolte e congelate con apparecchiature adeguate. Le cellule staminali periferiche sono le “cellule madri” delle cellule del sangue e, una volta raccolte e congelate in apposite sacche, potranno essere reinfuse per via venosa come una normale trasfusione al termine di una successiva chemioterapia ad alte dosi per facilitare la ricrescita dei globuli rossi, bianchi e delle piastrine nella fase di “aplasia” (caduta dei valori delle cellule del sangue) e per ridurre i rischi di infezione. Questa fase di terapia ad altissime dosi con reinfusione delle cellule staminali autologhe che verrà attuata successivamente è definita “autotrapianto”. La raccolta di cellule staminali verrà eseguita di norma dopo il 3° ciclo IGEV.

b. Ripetizione della PET al termine del 4° IGEV per valutare se è stata ottenuta la remissione (negatività PET).

c. Sulla base della PET effettuata dopo 4 IGEV la terapia prosegue nel modo seguente: - Casi PET negativi dopo IGEV: consolidamento con un solo autotrapianto di

cellule staminali, dopo una terapia ad alte dosi conosciuta con la sigla di BEAM.

- Casi PET positivi dopo IGEV: consolidamento con un autotrapianto (dopo una terapia con il farmaco melphalan ad alte dosi) seguito da un successivo trapianto allogenico non mieloablativo se vi è la disponibilità di un donatore sano HLA compatibile. Nel caso in cui non esista un donatore HLA compatibile si procederà a un secondo autotrapianto (dopo terapia ad alte dosi BEAM).

Per una maggiore garanzia sulla qualità della diagnosi PET, il giudizio positivo/negativo sarà dato da un gruppo di esperti Medici Nucleari che valuteranno il suo esame ed invieranno il loro giudizio alla segreteria del Centro di coordinamento dello studio in atto. La revisione centrale avverrà utilizzando un software non commerciale per la valutazione delle immagini mediche: il giudizio espresso dal gruppo di esperti sarà considerato valido per il proseguimento della terapia indipendentemente da quello del Medico Nucleare che ha effettuato l’indagine. Gli effetti collaterali che possono insorgere per i diversi schemi di chemioterapia sono principalmente: nausea, vomito, astenia, caduta dei capelli, mucosite con dolore alla


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bocca o allo stomaco, alterazioni dell’alvo. Dopo qualche giorno dall’infusione della chemioterapia si può verificare, anche in base all’aggressività del ciclo, un calo di globuli bianchi, globuli rossi e piastrine (pancitopenia). Gli schemi di chemioterapia ad alte dosi con autotrapianto provocano una vera e propria fase di aplasia midollare (i valori dei globuli scendono quasi a zero). Questa fase richiede quindi il ricovero sotto stretta osservazione, sarà fatta terapia con fattori di crescita e, quando necessario, sarà fatto un supporto trasfusionale. Il rischio di mortalità legato all’aplasia da trapianto autologo, se effettuato in centri adeguati, è ormai minimo e non supera anche nelle peggiori casistiche il 5%. I pochi pazienti che dovranno essere sottoposti a trapianto allogenico non mieloablativo correranno soprattutto i rischi legati alla GVHD (reazione del trapianto contro l’ospite o graft versus host disease). Per un periodo prolungato, anche dopo la dimissione, si renderà necessaria terapia immunosoppressiva. Oltre agli effetti indotti direttamente dalla GVHD su vari organi e in particolare su cute, fegato, intestino e polmone, è facile che si attivino infezioni virali (es citomegalovirus, herpes zoster, Ebstein Barr ecc), micotiche o da altri germi opportunistici (es. pneumocistis Carinii) legate all’importante terapia immunosoppressiva che deve essere attuata. La mortalità globale del trapianto allogenico legata a queste complicanze varia con l’età dei pazienti, ma non è indifferente e a seconda delle casistiche si può aggirare sul 15-20%. Per ridurre l’incidenza delle complicanze infettive è previsto l’impiego di un’adeguata terapia antibiotica di profilassi e, se necessario, di un supporto con immunoglobuline endovena. Viene inoltre informato del fatto che: • Potrà in ogni momento liberamente decidere di interrompere il trattamento intrapreso e

chiedere un cambiamento di terapia, assumendosi la responsabilità della decisione, senza che questo possa determinare alcuna conseguenza sull’assistenza medica e infermieristica che continuerà comunque ad esserle prestata.

• In caso di risposta insoddisfacente o cattiva tolleranza le saranno offerte tutte le alternative terapeutiche possibili spiegandole vantaggi ed inconvenienti.

• Si potrà avvalere in ogni momento della consulenza del suo medico di fiducia. • Sarà costantemente informato dai medici sul suo andamento clinico. • Non le sarà chiesto nessun carico di natura finanziaria • Una parte degli esami di laboratorio che le saranno eseguiti potranno essere utilizzati

per ulteriori indagini al fine di conoscere meglio gli effetti biologici della terapia. • I dati e le informazioni che avranno origine da questo studio saranno raccolti, analizzati

e trasmessi alla comunità medico-scientifica nel rispetto della legge DL 196 del 30 giugno 2003 che disciplina il diritto alla riservatezza. In particolare, ai sensi dell’art. 10 della citata legge, i dati personali da lei forniti ed in particolare quelli sensibili, saranno utilizzati nel rispetto della normativa sopra richiamata, oltre che delle vigenti leggi e degli obblighi alla riservatezza a cui si è ispirata la politica operativa dei medici curanti, allo scopo di migliorare le conoscenze e la terapia di questa malattia.

Il protocollo dello studio che le è stato proposto è stato redatto in conformità alle Norme di Buona Pratica Clinica dell’Unione Europea e alla revisione corrente della Dichiarazione di Helsinki. Il protocollo, il foglio informativo e il modulo di consenso informato di questo studio sono stati valutati e approvati dal Comitato Etico della Struttura Sanitaria a cui fa riferimento il medico responsabile dello studio e dalle competenti Autorità Sanitarie.

Lei potrà trattenere la parte informativa di tale documento. Per qualsiasi problema o per ulteriori informazioni su questo studio, potrà rivolgersi a:


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Dr_______________________________ Recapito telefonico___________________ Firma del paziente per presa visione_______________________________

Appendix P.

Codice sperimentazione IIL-HD0801

CONSENSO INFORMATO

Titolo dello studio: “Salvataggio precoce con chemioterapia ad alte dosi e trapianto di cellule staminali nel linfoma di Hodgkin con PET positiva dopo i primi 2 cicli di chemioterapia ABVD e paragone, nei casi PET-2 negativi trattati con 6 ABVD, di consolidamento con radioterapia sulle aree bulky verso sospensione della terapia”. Io sottoscritto Sig./Sig.ra____________________________________________________ Nato a_________________________________________________il_________________ Residente a_____________________________________telefono___________________ Sono stato/a informato/a dal Dr.______________________________________________ della natura della mia malattia. Si tratta di un Linfoma di Hodgkin in stadio avanzato. Mi è stato proposto di partecipare volontariamente allo Studio IIL-HD0801 che prevede una modulazione della successiva terapia sulla base della risposta (valutata con la PET) dopo i primi 2 cicli ABVD. Dichiaro di aver ricevuto dal Dr_______________________esaurienti spiegazioni in merito alla richiesta di partecipazione alla ricerca, in particolare sulle finalità e procedure. Dichiaro di aver avuto a disposizione tempo sufficiente per poter leggere attentamente, comprendere ed eventualmente farmi spiegare quanto contenuto nella scheda informativa allegata e da me sottoscritta per presa visione, e che conferma quanto mi è stato spiegato a voce, in particolare che la sperimentazione sarà condotta nel rispetto dei codici etici internazionali. Dichiaro di aver avuto la possibilità di porre domande e di aver avuto risposte soddisfacenti su tutta la sperimentazione ed in particolare sulle possibili alternative diagnostiche e terapeutiche e sulle conseguenze della mancata esecuzione della procedura proposta. Sono stato/a informato/a e sono consapevole che la partecipazione è volontaria; il rifiuto a partecipare allo studio non influirà nel ricevere il trattamento più idoneo. Sono stato/a inoltre informato/a che: • Potrò ritirarmi dalla sperimentazione già iniziata in qualsiasi momento, senza

conseguenze negative nel ricevere il trattamento più idoneo e senza l’obbligo da parte mia di motivarne la decisione, a meno che la stessa non derivi dalla comparsa di disturbi o effetti indesiderati e/o non previsti, nel qual caso mi impegno fin da ora a comunicarne tempestivamente al medico sperimentatore natura ed entità.


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50

• Potrò in ogni momento liberamente decidere di interrompere il trattamento intrapreso e chiedere un cambiamento di terapia, assumendomi la responsabilità della decisione, senza che questo possa determinare alcuna conseguenza sull’assistenza medica ed infermieristica che continuerà comunque ad essermi prestata.

• In caso di risposta insoddisfacente o cattiva tolleranza mi saranno offerte tutte le alternative terapeutiche possibili spiegandomene vantaggi ed inconvenienti.

• Mi potrò avvalere in ogni momento della consulenza del mio medico di fiducia. • Sarò costantemente informato dai medici sul mio andamento clinico. • In caso di discrepanza fra il giudizio espresso dal gruppo di esperti e quello dello

specialista che ha eseguito la PET, sarà preso in considerazione solo il giudizio del gruppo di esperti per il proseguimento della terapia.

• Non mi sarà chiesto nessun carico di natura finanziaria. Acconsento altresì che i dati e le informazioni che avranno origine da questo studio siano raccolti, analizzati e trasmessi alla comunità medico-scientifica nel rispetto della legge DL 196 del 30 giugno 2003 che disciplina il diritto alla riservatezza. In particolare, ai sensi dell’art. 10 della citata legge, sono informato che i dati personali da me forniti ed in particolare quelli sensibili, saranno utilizzati allo scopo di migliorare le conoscenze e la terapia di questa malattia nel rispetto della normativa sopra richiamata, oltre che delle vigenti leggi e degli obblighi alla riservatezza a cui si è ispirata la politica operativa dei medici curanti. Sono stato/a informato/a che per ogni problema o per eventuali ulteriori informazioni potrò

rivolgermi al:

Medico Sperimentatore Dr_______________________________

Recapito telefonico___________________

Pertanto confermo di aver avuto risposte esaurienti a tutti i miei quesiti e, preso atto della situazione illustrata,

ACCONSENTO LIBERAMENTE, SPONTANEAMENTE E IN PIENA COSCIENZA ALLA SPERIMENTAZIONE PROPOSTAMI. Dichiaro inoltre di essere a conoscenza della possibilità di revocare il presente consenso in qualsiasi momento prima dell’avvio della sperimentazione. Data_________________________________Ora _______________________________ Firma del paziente_________________________________________________________ Firma del medico _________________________________________________________


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Eventuali testimoni presenti (nome, cognome, firma):______________________________

OPPURE

NON ACCONSENTO LIBERAMENTE, SPONTANEAMENTE E IN PIENA COSCIENZA ALLA SPERIMENTAZIONE PROPOSTAMI. CONSAPEVOLE DEI RISCHI DERIVANTI DAL RIFIUTO A SOTTOPORMI ALLA STESSA. Data_________________________________Ora _______________________________ Firma del paziente_________________________________________________________ Firma del medico _________________________________________________________ Eventuali testimoni presenti (nome, cognome, firma):______________________________


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Appendix Q. Grading of toxicity

Toxicity will be evaluated according to Common Terminology Criteria for Adverse Events

(CTCAE) v 3.0 (updated August 9, 2006).

Online instructions and guidelines are available on the website of the National Institute of

Health (NIH): http://ctep.cancer.gov/reporting//ctc.html or on the site

http://www.epiclin.cpo.it.

http://ctep.cancer.gov/reporting//ctc.html

http://www.epiclin.cpo.it/


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Appendix R. Criteria and Instructions for PET evaluation and revision PET working party. Antonio Castagnoli, Giannetto Comis, Alberto Pupi Timing of Interim PET Scan The Interim FDG-PET scan should be planned in advance: at least 7-10 days after day 15 of the second cycle of ABVD. In case of use of G-CSF, the scan should non be planned before 48 hours since stop of G-CSF, to avoid false positive scan. Patient Preparation. Patients should be fasting for at least 6 hours and drinking about 2 litres of water prior to tracer injection. Patients should have free access to all normal medication but withdrawal of corticosteroid 24 hours prior to tracer injection. The day before FDG-PET scanning patients should avoid eating carbo-hydrate . The weight and height of the patients will be recorded. Blood glucose leveles must be assessed prior to tracer injiection ; patients with blood glucose level above 200 mg % will be discarded. In case of anxiety benzodiazepine or beta-blockers are permitted and patients should remain still in a quite room just prior injection; warm cloth are recommended between tracer injection and scanning to prevent muscles and/or brown fat uptake. A butterfly or venous catheter is placed in a vein of the forearm; 250 -500 ml of saline will be delivered after tracer injection to flush the catheter and keep the patient well hydrated. Patient will drink two or three glass of water before scanning. Technical Requirements FDG-PET scan will be performed with a modern full-ring dedicated PET scanner. PET/CT scanners are recommended. Each patient is scanned in the same camera with the same acquisition protocol. Acquisition Protocol A dose of approximately 185 MBq- 550 MBq is administered intravenously as a bolus according to routine clinical acquisition protocol for that specified PET scanner. Tracer activity and time of injection is recorded in the case record form. Prior to the scanning the patient is asked to void. A whole-body acquisition with attenuation correction and with emission scan is started 60-90 minutes after injection, starting to groin up to the ears. The time of the commencement of the scan is recorded in the case record form. Time for bed position is dependent on the PET machine and will be left open: it was recorded in the case report form. PET reconstruction Scan data will be recorded for decay, body weight and administered activity and reconstructed using an iterative algorithm. PET analysis. The PET scans will be analyzed using a visual assessement. The FDG-PET scans will be displayed in both projection and volume views, the latter using coronal, sagittal and transaxial views. Displaying of fused images is recommended to allow improvement of


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data interpretation. The PET scans are anyway scored with knowledge of the CT and clinical data available. The PET results must be scored according to a two point visual scoring system: O: negative / normal / minimal residual uptake/ benign 1 : positive/ malignant Minimal residual uptake is defined as low grade uptake of FDG ( just above background) in a focus within an area of previously noted disease, regarded as not likely to represent malignancy. Mild and diffusely increased FDG uptake at the site of moderate or large-sized residual masses ( ≥ 2 cm in diameter) with intensity lower than or equal to that of mediastinum should be considered negative for presence of residual lymphoma. The use of mediastinum as a “reference background tissue” only applies to attenuation-corrected scans. In interim scan it is to consider that uptake in “non active” residual mass may be higher than expected owing to the effect of chemotherapy or healing processes and liver uptake as reference background may be proposed ( Huchings personal communication): the opinion of the writing committee is that given this particular patient population, a false positive PET scan is less dangerous than a false negative one and mediastinum as background has been preferred. A positive PET is defined as a scan with FDG-uptake focus exceeding the normal FDG uptake considering anatomy/physiology in previously diagnosed sites or new sites, which is considered to represent malignancy. A positive PET scan is considered also mild and diffusely increased FDG uptake in nodal residual masses less than 2 cm with intensity lower than or equal to that of mediastinum Lymph-nodes are considered as basin not as single node. Focal uptake diagnosed as benign, like simmetrical cervical uptake suggesting flogosis will be rated as negative and described in the section “note”. New lung nodules ≥ 1.5 in diameter at CT scan should be considered positive for disease if uptake largerly exceed that of mediastinum unrespective of evidence of pulmonary lymphoma before therapy or equal to mediastinum if in site of previous disease: otherways it should be considered negative because of the possibility of infectious or inflammatory lesions. Diffusely increased uptake in the spleen, greater than that of normal liver, should be regarded as positive for lymphoma is the patient is out from cytochines administration since at least 10 days. Uptake in bone should be considered compatible with lymphoma only if clearly focally increased, while diffuse uptake, even if more intense than the liver, is usually due to post-therapy hyperplasia. Central Review. A treatment decision is made on the result of Interim PET scan. Therefore it was decided to make a central PET review. Central PET review is planned for all PET scans to reduce the variability of visual scan interpretation between various readers. PET review is mandatory in order to plan the subsequent treatment when the local nuclear medicine gives a “grey” result, with minimal residual uptake. In this group of patients, while waiting for central panel review, the first course of the third ABVD will be administered, but the subsequent treatment will be based on the central PET review panel opinion. Central review will take place as soon as possible and within five days from PET scan. A system is presented that could make be possible to view imaging studies securely by internet. This system will use an open source software from NIH (see Appendix S). A team of 11 nuclear medicine specialist will be installed as reviewers. Ideally the reviewing process will proceed as follows:


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The local nuclear medicine specialist will send the initial and interim PET scans and CT scans to a central imaging core laboratory (server) as DICOM files and will give notification by e-mail to all reviewers that a case has been submitted for review, along with available clinical informations reported in the case report form. The scans are coded. The reviewers download all the scans from server on their own viewing machine, review the case, and send the results on the form to the HD07 data center. Once the HD07 data center has received an answer from 5 reviewers the case is close. The local physician will be informed of the result. In case of discrepancy between the local and central nuclear medicine specialist the result of the central review will win.


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HD08a Case Report Form

Centro Proponente:……………………

Medico Referente:…………………………………………………..tel.:………………………….

Medicina Nucleare di Riferimento:…………………………………tel.:………………………

PET scanner:………………………

Durata lettino:…… …min Traccia Standard: . ….. …… MBq/Kg

Cognome…………………………..Nome………………………………Codice…………………. Stadio: …………………….. Clinica alla presentazione:……………………………………… ……………………………………………………………………………………………………… Data di nascita (gg/mm/aa) |_|_| |_|_| |_|_| Note ……………………………………………………………………………… ……………………………………………………………………………………………………. ……………………………………………………………………………………………………. Data PET Basale (PET-0) (gg/mm/aa) |_|_| |_|_| |_|_| Dose traccia: MBq sede iniezione………….attesa…………min Glicemia………… Esito: 0 , 1 Sede: SM1,SM2,LC1,LC2,SC1,SC2,AS1,AS2,IN1,IN2 MS,M1,LA,BA,AP,IP1,IP2,IS,IE,LT,LA1,LA2,IL1,IL2 P,F,BM Note ……………………………………………………………………………… ……………………………………………………………………………………………………. ……………………………………………………………………………………………………. Revisore:………………………………………. Data PET Precoce (PET-2) (gg/mm/aa) |_|_| |_|_| |_|_| Data somministrazione ultima dose di Chemioterapia (gg/mm/aa) |_|_| |_|_| |_|_| Esito: 0 , 1 Sede: SM1,SM2,LC1,LC2,SC1,SC2,AS1,AS2,IN1,IN2 MS,M1,LA,BA,AP,IP1,IP2,IS,IE,LT,LA1,LA2,IL1,IL2 P,F,BM Note ……………………………………………………………………………….. ……………………………………………………………………………………………………. ……………………………………………………………………………………………………. Revisore:………………………………………. Data PET post IGEV (PET- 4 ) (gg/mm/aa) |_|_| |_|_| |_|_| Data somministrazione ultima dose di IGEV (gg/mm/aa) |_|_| |_|_| |_|_| Esito: 0 , 1 Sede: SM1,SM2,LC1,LC2,SC1,SC2,AS1,AS2,IN1,IN2 MS,M1,LA,BA,AP,IP1,IP2,IS,IE,LT,LA1,LA2,IL1,IL2 P,F,BM Note ……………………………………………………………………………….. …………………………………………………………………………………………………….……………………………………………………………………………………………………. Revisore:……………………………………….


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CODIFICA DELLE SEDI

SM1:sottomandibolare dx SM2: sottomandibolare sx LC1: laterocervicali destri LC2:laterocervicali sinistri SC1:sovraclaveari destri SC2:sovraclaveari sinistri AS1:ascellari destri AS2:ascellari sinistri IN1:inguinali destri IN2:inguinali sinistri

MS:mediastino superiore MI:mediastino inferiore AO:linfonodi aortici BA: Linfnd Barety AP: finestra aorto-polmonare IP1:ilo destro IP2:ilo sinistro

IS:ilo splenico IE:ilo epatico LT:linfonodi tripode celiaco LA1:lomboaortici destri LA2:lomboaortici sinistri IL1iliaci destri IL2:iliaci sinistri P:Polmone F:Fegato BM:Midollo


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Appendix S. Instructions for PET Central Review. This section is written in italian language for Italian users because it is only a technical note.

Central Review Working Party Alberto Pupi*, Antonio Castagnoli,Giannetto Comis.* Formato dei file Per ragioni di omogeneità di lettura da parte dei centri che partecipano alla central review, sarà opportuno limitare i formati di file ai due tipi più diffusi in questo ambito, e cioè DICOM (come file singolo oppure come multifile) e Analyze (coppie ‘.hdr’ e ‘.img’). Immagini eventualmente disponibili in formati diversi dovrebbero essere convertite in uno di questi due formati prima di effettuarne l’upload. Accesso al sito FTP per l’upload e il download degli studi Presso la Medicina Nucleare di Firenze è stato installato un server FTP destinato a raccogliere in maniera centralizzata tutti gli studi PET-TC destinati ad entrare a far parte della central review. La connessione al sito può avvenire sia in modalità FTP sia in modalità SSH. I parametri di connessione sono:

host name med1nuc31.dfc.unifi.it IP address 150.217.103.72 user unificentralreview password viola*07

Per effettuare l’upload degli studi, è preferibile innanzitutto creare una cartella con il nome della città che ospita il centro che si accinge ad effettuare l’upload (ad esempio “Reggio_Emilia”, “Firenze”, ecc.) e, all’interno di tale cartella, creare una ulteriore cartella per ciascun paziente, identificata da un codice univocamente attribuito. All’interno di quest’ultima sarà poi utile suddividere in due cartelle distinte la PET e la TC, soprattutto nel caso in cui esse vengano fornite in formato DICOM multifile. A giudizio del gruppo responsabile del caso, potrà infine essere opportuno provvedere all’ anonimizzazione degli studi prima di effettuarne l’upload. Istruzioni dettagliate per l’anonimizzazione di uno studio in formato DICOM con il programma di imaging MIPAV sono fornite nel seguito di questa bozza. Per una connessione più sicura, tanto in upload quanto in download, è preferibile impiegare il protocollo SSH. Un package per Windows di larga diffusione e’ SSH Secure File Transfer, scaricabile dal sito:

http://www.ssh.com/support/downloads/secureshellwks/non-commercial.html L’impiego di SSH Secure File Transfer è estremamente semplice. Una volta terminata l’installazione, appaiono sul desktop di Windows due icone: si deve cliccare sull’icona gialla “SSH Secure File Transfer Client”. Dalla finestra principale del programma si attiva direttamente la connessione cliccando su “Quick Connect”. I dati da inserire nella finestra di dialogo che appare sono:

Host Name med1nuc31.dfc.unifi.it (oppure 150.217.103.72)

User Name unificentralreview Port Number 22

http://www.ssh.com/support/downloads/secureshellwks/non-commercial.html


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Authentication Method <Profile Settings> (gli ultimi due sono già presenti per default). Dopo qualche secondo dovrebbe apparire una nuova finestra di dialogo con la richiesta della password. Inserire “viola*07”. Cliccare su “Ok”. La prima volta che ci si connette ad un nuovo server possono apparire altre richieste di conferma dell’operazione in corso: proseguire sempre con la connessione. A connessione avvenuta, nella fascia centrale della finestra principale, a destra, dovrebbero apparire le cartelle relative ai vari centri partecipanti alla central review (ad esempio: “Firenze”, “Reggio_Emilia”, ecc.). Si prosegue l’operazione cliccando sulla cartella che interessa. A questo punto è possibile effettuare l’upload di uno studio, cioè il trasferimento dello studio dal proprio computer al server della central review, oppure il download, cioè il trasferimento dal server al proprio computer. Per l’upload, è consigliabile disporre sul proprio computer di una cartella (avente un nome atto ad identificare univocamente lo studio), già contenente la PET e la TC in formato DICOM oppure Analyze. Se il formato è DICOM multifile (cioè un file per ciascuna slice), è necessario suddividere la PET e la TC in due sottocartelle. Una volta predisposta tale cartella, per trasferirla sul server è sufficiente spostarla nella parte centrale destra della finestra di SSH Secure File Transfer (quella con la dicitura “Remote name”): il progresso del trasferimento è visibile nella parte bassa della finestra (“Transfer”). Al termine si chiude SSH. Per il download si tratta invece di cliccare con il pulsante destro sulla cartella con lo studio da trasferire e selezionare “Download dialog”, aprire la cartella del computer locale dove deve essere indirizzato il trasferimento, e infine cliccare su “Download”. Anche in questo caso si può seguire l’andamento del trasferimento nella parte bassa della finestra principale di SSH Secure File Transfer. Al termine si può chiudere il programma. Per chi dispone di un computer Linux, esistono numerosi tools per l’upload e il download in SSH, nel dettaglio dei quali non entriamo in questa sede. Un esempio tra i più user friendly, per gli utenti che dispongono dell’interfaccia grafica KDE, è costituito da fish, un tool integrato all’interno del browser Konqueror. E’ sufficiente digitare nel campo degli indirizzi di Konqueror:

“fish://[email protected]” oppure

“fish://[email protected]” e inserire successivamente la password “viola*07” quando richiesta. Impiego del package MIPAV per la visualizzazione ed elaborazione degli studi Sono disponibili numerosi package di imaging, commerciali o disponibili gratuitamente, che consentono di svolgere le funzioni richieste dalla central review. Qui di seguito si descrive una sessione di esempio per la quale è stato impiegato il package MIPAV (Medical Image Processing, Analysis and Visualization), realizzato e mantenuto dal CIT (Center for Information Technology) presso i National Institutes of Health di Bethesda (USA). MIPAV è scritto in linguaggio Java, ed è pertanto disponibile per tutte le piattaforme Java-enabled (e in particolare per Windows, Linux, Unix, Macintosh OS X). Il download è gratuito (sono richieste soltanto le generalità e l’indirizzo di e-mail) e può essere effettuato dal sito:

http://mipav.cit.nih.gov/

http://mipav.cit.nih.gov/


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Sul medesimo sito è disponibile un’ampia e curata documentazione: manuale completo in due volumi, linee guida per le operazioni più comuni o più complesse, ecc. Una volta effettuato il download dell’ eseguibile autoinstallante relativo alla propria piattaforma, per effettuare l’installazione è sufficiente seguire le semplici istruzioni fornite. C’è un’unica operazione aggiuntiva richiesta al momento della prima esecuzione: si tratta di riservare a MIPAV la maggior quantità possibile di RAM (il valore deve essere digitato in un’apposita finestra di dialogo che si apre automaticamente). In linea di principio conviene fornire un valore pari a metà della RAM in dotazione al computer se si impiega Windows, salendo eventualmente fino al 60-70% se invece si impiega Linux. In ogni caso non si deve fornire l’intera RAM disponibile, altrimenti MIPAV può riavviarsi in modalità non corretta e può essere necessario disinstallarlo e ripetere l’installazione. Per quanto riguarda la configurazione minima richiesta per il computer sul quale si intende installare il programma, va tenuto presente che MIPAV è estremamente “vorace” per quanto riguarda le risorse (CPU e RAM): per piattaforme Intel è necessario orientarsi su CPU di classe Pentium 4 o superiore (Core Duo, ecc.), mentre la quantità di RAM varia molto a seconda del numero e della dimensione delle immagini da trattare, nonché del tipo di elaborazione da effettuare. Tra i sistemi operativi testati per l’impiego di MIPAV, Linux si è dimostrato, sotto diversi aspetti, più robusto di Windows e in grado di sfruttare meglio le risorse del computer: il suo impiego è quindi fortemente consigliato, in particolare per lo svolgimento delle elaborazioni più impegnative. Tanto per fornire un esempio, per il caricamento di una TAC 512x512 e di una PET 128x128 e per la successiva fusione dei due volumi (nonché per la visualizzazione triplanare dei medesimi) si sono dimostrati necessari almeno 3 GB di RAM su un PC Pentium 4, con sistema operativo Linux o Windows.

Anonimizzazione di uno studio MIPAV consente di anonimizzare uno studio, purché in formato DICOM, prima di effettuarne l’upload sul server della central review. Allo scopo può essere impiegata la funzione “File / DICOM / Anonymize DICOM directory”. Innanzitutto si deve selezionare la cartella contenente lo studio da anonimizzare:

Si apre una finestra di dialogo. Nel folder “Directory” si deve selezionare la “Image source directory” nonché impostare la “Image destination directory”:

e nel folder “Tag options” si devono selezionare gli elementi da anonimizzare:


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e quindi premere il pulsante “Run”. Alla seconda esecuzione della procedura di anonimizzazione sullo stesso paziente (ad esempio quando si anonimizza la TC dopo aver effettuato la stessa operazione sulla PET) appare una finestra del tipo:

nella quale si può senz’altro rispondere “Overwrite”. Al termine, nella cartella impostata in “Image destination directory”, sarà disponibile lo studio DICOM con gli elementi richiesti anonimizzati.


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Sessione di visualizzazione ed elaborazione di uno studio PET-TC Qui di seguito si forniscono, a titolo di esempio, le istruzioni dettagliate per il caricamento, la fusione e la visualizzazione ed esplorazione triplanare sincronizzata di uno studio PET-TC (con PET 128x128 e TC 512x512, entrambe in formato DICOM), effettuati con MIPAV su un PC Pentium 4 con 3 GB di RAM (di cui 1.2 circa riservati a MIPAV) e sistema operativo Windows. La prima operazione consiste nel caricamento in memoria delle immagini DICOM. Ciò avviene mediante la funzione “File / DICOM / DICOM browser”. Si seleziona la cartella contenente lo studio DICOM richiesto e la si apre (si inizia per esempio dalla TC):

Nella finestra di dialogo “DICOM browser” si seleziona nuovamente la cartella in alto a sinistra:


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quindi si clicca sull’icona “Parse directory” (la seconda da sinistra):

si ordinano le slice dello studio per posizione sull’ asse Z crescente (cliccando su “Z-position”):


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si selezionano tutte le slice con l’icona “Select all rows” (ultima a destra):

e infine si carica e visualizza lo studio con l’icona “Open selected image(s)” (la prima a sinistra). L’operazione può richiedere qualche tempo; a seconda della versione di MIPAV impiegata, può apparire o meno una barra di caricamento: in ogni caso, fintantoché il caricamento è in corso, lo sfondo dell’icona rimane azzurrino.


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A questo punto si può convertire lo studio in formato Analyze con la funzione “File / Save image as”. E’ sufficiente impostare una cartella adatta e un nome con estensione “.img”. Verranno creati due file Analyze (“.hdr”, contenente l’header e “.img”, contenente i dati):

Si può chiudere l’immagine CT ed effettuare la stessa operazione per la PET. Al termine si caricano nuovamente CT e PET in formato Analyze con “File / Open image (A) from disk …”:


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Le due immagini saranno quindi entrambe visualizzate. Per ottimizzare i parameri di visualizzazione è sufficiente aprire e richiudere la finestra di dialogo “Level & Window” mentre l’immagine che si desidera modificare è attiva. L’icona e’ quella grigio-bianca con le lettere “ “W L”:

A questo punto si può ridimensionare l’immagine PET per ottenere nel seguito una sovrapposizione di miglior qualità. Allo scopo si deve renderla attiva (cliccandovi sopra) e usare la funzione “Algorithms / Transformation tools / Transform”. Nella finestra “Transform / resample image” selezionare “User defined size” e impostare per “DimX” un valore, ad esempio, di 256:

al termine dell’esecuzione, apparirà l’immagine PET ricampionata a 256x256 pixel. Si può chiudere l’immagine PET 128x128.


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Si procede rendendo attiva la nuova immagine PET (sempre cliccandovi sopra) e quindi caricandovi sopra l’immagine TC. Ciò può essere fatto con la funzione “File / Load image (B) / From frame”, lasciando la spunta soltanto su “Use image origin information to align images”:

L’operazione può richiedere un tempo relativamente lungo, e comporta la disponibilità di una considerevole quantità di memoria. Al termine, l’immagine TC appare sovrapposta all’immagine PET. Per maggior chiarezza può essere utile modificare la LUT della PET, ad esempio applicando una scala a falsi colori (per la LUT “Hot metal” è direttamente disponibile l’icona a fasce verticali nere-rosse-gialle, altrimenti la LUT può essere scelta e modificata a piacere con la funzione “LUT / Histogram – LUT …”, accessibile anche dall’icona con il grafico a colori):

Quando è attiva la finestra con la TC sovrapposta alla PET, la finestra principale di MIPAV si modifica, offrendo, al disotto della barra di selezione della slice (“Image slice”) un’altra barra (“Active Image and Alpha Blending”) che consente di scegliere il contributo di ciascuna delle due immagini sovrapposte:


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E’ infine possibile ottenere una visualizzazione triplanare (assiale – sagittale – coronale), con cursori sincronizzati, della TC, della PET e dell’immagine combinata. La funzione da impiegare è “Image / Views / Triplanar”:

MIPAV è estremamente potente e versatile: sono perciò naturalmente possibili infinite variazioni ed ulteriori elaborazioni rispetto alla modalità operativa di base esposta in questo esempio. E’ disponibile un manuale utente molto dettagliato in due volumi, scaricabile in formato PDF:

MIPAV User’s guide – Volume 1 – BASIC MIPAV User’s guide – Volume 2 – ALGORITHMS

Per necessità tecniche contattare Giannetto Comis, , Medicina Nucleare Biomolecolare, AOU Careggi, Firenze ([email protected]) * Medicina Nucleare Biomolecolare, AOUC Careggi, Firenze


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Fondazione Intergruppo Italiano Linfomi-ONLUSDec 05, 2008 · E-mail: [email protected] •...

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Transcript of Fondazione Intergruppo Italiano Linfomi-ONLUSDec 05, 2008 · E-mail: [email protected] •...